Compounds from renewable resources

ABSTRACT

Compounds of formula III: 
     
       
         
         
             
             
         
       
     
     and salts thereof are disclosed. Also disclosed are methods for preparing compounds of formula III, intermediates useful for preparing compounds of formula III and methods for preparing compounds and materials from compounds of formula III.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/320,087 that was filed on Apr. 8, 2016. The entire content of theapplication referenced above is hereby incorporated by referencedherein.

BACKGROUND

Itaconic acid (or itaconate, depending on its prevailing ionizationstate; Medway, A. M., Sperry, Green Chem. 2014, 16, 2084-2101) andfurfural (Cai, C. M., et al., J. Chem. Technol. Biotechnol. 2014, 89,2-10) are two chemicals abundantly available from biomass. They areprominent entries on master lists of privileged compounds for potentialuse in preparing bio-sourced/sustainable/renewable polymers andmaterials (e.g., Ritter, S. K., Chem. Eng. News 2004, 82, 31-34; Topvalue added chemicals from biomass, Volume I-Results of screening forpotential candidates from sugars and synthesis gas. eds. Werpy T.,Petersen, G., US Department of Energy, 2004.nrel.gov/docs/fy04osti/35523.pdf (accessed Jan. 15, 2016)). The firstarises by metabolic pathways as textbook as the citric acid (also knownas the tricarboxylic or Krebs) cycle; the second by acid-catalyzeddehydration of 5-carbon sugars prevalent in, for example, corncobs(Adams, R., Voorhees, V., Organic Syntheses, Vol. 1, 1921, 49) and oathusks. For a century it has been known that each of itaconic anhydride(1, IA) and furfuryl alcohol (2, FA) is readily available by simpleconversions such as dehydration (Fittig R., et al., J. Liebigs Ann.Chem. 1904, 331, 151-196) and reduction (Kaufmann W. E., Adams, R., J.Am. Chem. Soc. 1923, 45, 3029-3044) of these abundantly availableprecursors (Scheme 1).

The Diels-Alder (DA) [4+2] cycloaddition reaction to produce cyclohexenederivatives is among the most iconic of all reactions in organicchemistry. The ability of IA to function as a dienophile, the2π-component, to engage various dienes was, in fact, described in theground-breaking first publication by Diels and Alder (Diels O., AlderK., J. Liebigs Ann. der Chem. 1928, 460, 98-122). The use of furan as adiene, the 4π-component, was reported one year later in their secondpaper on the subject of “hydroaromatic synthesis” (Diels O., K., Ber.Dtsch. Chem. Ges. 1929, 62, 554-562). It appears that there have been noreports regarding the reaction of IA (1) or itaconic acid (or itsesters) with any furan derivative in the intervening >85 years. A recentstudy of the DA reactions of 2-methyl- and 2,5-dimethylfuran with maleicanhydride, a more reactive, bio-derivable anhydride, has been reported(Mahmoud E., et al., Green Chem. 2014, 16, 167-175).

There is a continually growing interest in sourcing organic compoundsfrom renewable resources. Compounds from renewable resources may beuseful as such, or these compounds may be useful as intermediates toprepare other compounds or materials such as bio-sourced materials(e.g., polymers). The vast majority of plastics commonly used today(e.g., polyethylene and polystyrene) are produced from crude oil(petroleum) and natural gas. These plastics are widely used inapplications ranging from automotive, packaging, adhesive, andconstruction materials.

However, because they are derived from non-renewable feedstocks, theseare, necessarily, unsustainable materials. Alternatively, polymericmaterials derived from renewable raw materials (e.g., sugars,cellulosics, vegetable oil, and terpenes) that have comparableproperties to those of petroleum-derived polymers and plastics have thepotential to meet the needs (and desires) of humans while having zeronet impact on the earth's environment. Bio-soured plastics could findutility in essentially all of the myriad applications of today'splastics. Common chemical classes of polymers that can be bio-sourcedinclude polyolefins, polyesters, polyamides, polyurethanes, andpolycarbonates. Sustainable polymers or “green materials” can be bothdurable and degradable, they can be used in applications ranging fromadhesives to packaging to clothing to building materials, and they can,in principle, be produced both economically and with minimalenvironmental impact.

SUMMARY OF INVENTION

One embodiment provides a compound of formula I or a salt thereof, or acompound of formula II or an enantiomer thereof:

wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl and each dashed bondis a single bond or double bond provided no two double bonds of thecompound of formula II are cumulated.

One embodiment provides a compound of formula III or a salt thereof:

wherein: m is 1 or 2; R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl; andthe dashed bond is a single bond or double bond.

One embodiment provides a method for preparing a compound of formulaIc1:

or a salt thereof or an enantiomer or a salt thereof, comprisingconverting furfuryl alcohol to the compound of formula Ic1 or a saltthereof or an enantiomer or a salt thereof.

One embodiment provides a method for preparing a compound of formulaIc1:

or a salt thereof or an enantiomer or a salt thereof, comprisingconverting itaconic anhydride to the compound of formula Ic1 or a saltthereof or an enantiomer or a salt thereof.

One embodiment provides a method for preparing a compound of formulaIc1:

or a salt thereof or an enantiomer or a salt thereof, comprisingcontacting furfuryl alcohol with itaconic anhydride to provide thecompound of formula Ic1 or a salt thereof or an enantiomer or a saltthereof.

One embodiment provides a method for preparing a compound of formulaIIa:

or enantiomer thereof comprising converting a compound of formula Ic:

or a salt thereof or an enantiomer or a salt thereof to the compound offormula IIa wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a method for preparing a compound of formula 18:

comprising converting a compound of formula Ic:

or a salt thereof or an enantiomer or a salt thereof to the compound offormula 18, wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a method for preparing a compound of formula 18:

comprising converting a compound of formula IIa:

or an enantiomer thereof to the compound of formula 18.

One embodiment provides a method for preparing a compound of formula 23:

or a salt thereof, comprising converting a compound of formula Id:

or a salt thereof or an enantiomer or a salt thereof to the compound offormula 23, wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a polymer comprising two or more residues offormula 26:

or a salt thereof, wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a method for preparing a polymer comprising twoor more residues of formula 26:

or a salt thereof, comprising polymerizing a compound of formula I:

or a salt thereof, wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a method for preparing a polymer comprising twoor more residues of formula 26a:

wherein: m is 1 or 2; and R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl; ora salt thereof, comprising polymerizing a corresponding compound offormula III:

wherein: m is 1 or 2; R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a method for preparing a compound of formulaIIIc1:

or a salt thereof or an enantiomer or a salt thereof, comprisingconverting furfuryl alcohol to the compound of formula IIIc1 or a saltthereof or an enantiomer or a salt thereof.

One embodiment provides processes and intermediates disclosed hereinthat are useful for preparing a compound of formula I or useful forpreparing compounds from a compound of formula I.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows the GPC chromatograms of 26, entries 1 and 2 (Table 1).

FIG. 2 shows the DSC heating curves of 26, entries 1 and 2 (Table 1);data shown are for the second heating cycle (10° C.·min⁻¹).

FIG. 3 shows the MALDI mass spectrum of 26, entry 1 (Table 1).

FIG. 4 shows the equilibrium state ¹H NMR spectrum for formation of4-endo and 4-exo.

FIG. 5 shows the equilibrium state ¹H NMR spectrum for formation of7-endo and 7-exo.

FIG. 6 shows the equilibrium state ¹H NMR spectrum for formation of9-dist-endo, 9-dist-exo, 9-prox-endo, and 9-prox-exo.

FIG. 7 shows the equilibrium state ¹H NMR spectrum for formation of11-dist-endo, 11-dist-exo, 11-prox-endo, and 11-prox-exo.

FIG. 8 shows the in situ ¹H NMR monitoring of the reaction of 14 inCDCl₃ to produce 15a and 15b via 1 and 2 (and, presumably, 12-prox-exo).

FIG. 9 shows the diagnostic trends in NMR data that for 4-exo vs. 4-endothat were used to deduce and assign the relative configuration within DAadducts 7, 9, and 11.

FIGS. 10A and 10B show the CMAEs for ¹H (10A) and ¹³C (10B) computedchemical shifts between matched and unmatched 4-exo-h2 and 4-endo-h2.

FIGS. 11A and 11B show the CMAEs for ¹H (11A) and ¹³C (11B) computedchemical shifts between matched and unmatched 4-exo and 4-endo.

FIG. 12A shows the rate and final equilibrium resting state for the DAreaction between IA (1) and furan (3) and the conversion of 4-endo to 5via 4-endo-h2.

FIG. 12B shows the 3D structure of 5 from a single crystal X-rayanalysis.

FIG. 13 shows the 1H NMR spectrum in acetone-d6 of an aliquot of thebulk reaction mixture from 1:1 IA (1) and FA (2). For spectrum A theresonances from the major product 14 are assigned. For spectrum b thevertical scale has been increased 5× and the principal minor componentsare denoted. Integration of all minor components indicates a 94% yieldof 14.

FIG. 14 shows the preparation of compounds 100, 200, and 300, as furtherdescribed in Examples 2, 3, and 4.

FIG. 15 shows the polymerization of compounds 100 and 200, as furtherdescribed in Examples 5 and 6.

FIG. 16 shows the polymerization of compound 200 under RAFT conditions,as further described in Example 7, and 300.

FIG. 17 shows the polymerization of compound 300, as further describedin Example 8.

FIG. 18 illustrates compounds and synthetic processes of the invention.

FIG. 19 shows the Tg for the material prepared at Example 5.

FIG. 20 shows the Tg for the material prepared at Example 7.

FIG. 21 shows the retention time for the material prepared at Example 7.

FIG. 22 shows the Tg for the material prepared at Example 8.

DETAILED DESCRIPTION

Described herein is the discovery of highly versatile organic compounds(e.g., compounds of formula I) that are sourced from renewableresources. Also described herein are methods to prepare such compounds(e.g., compounds of formula I) and methods to prepare other compoundsand materials from such compounds.

The following definitions are used, unless otherwise described.

The term “alkyl” refers to a straight or branched saturated hydrocarbon.For example, an alkyl group can have 1 to 8 carbon atoms (i.e.,(C₁-C₈)alkyl) or 1 to 6 carbon atoms (i.e., (C₁-C₆ alkyl).

The term “cycloalkyl” refers to a cyclic saturated hydrocarbon. Forexample, (C₃-C₆)cycloalkyl can have 3 to 6 cyclic carbon atoms.

The term “cumulated” as used herein refers to carbon-carbon double bondsthat share a carbon atom.

It will be appreciated by those skilled in the art that compounds of theinvention having one or more chiral centers may exist in and be isolatedfor example in optically active and racemic forms. Some compounds mayexhibit polymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of the inventionthat possess the useful properties described herein, it being well knownin the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by enantioselectivesynthesis methods (including asymmetric catalysis), or bychromatographic separation using a chiral stationary phase.

When a bond in a compound formula herein is drawn in anon-stereochemical manner (i.e., flat), the atom to which the bond isattached includes all stereochemical possibilities. When a bond in acompound formula herein is drawn in a defined stereochemical manner(i.e., bold, bold-wedge, dashed, or dashed-wedge), it is to beunderstood that the atom to which the stereochemical bond is attached isenriched in the absolute stereoisomer depicted unless otherwise noted.In one embodiment, the compound may be at least 51% the absolutestereoisomer depicted. In another embodiment, the compound may be atleast 60% the absolute stereoisomer depicted. In another embodiment, thecompound may be at least 80% the absolute stereoisomer depicted. Inanother embodiment, the compound may be at least 90% the absolutestereoisomer depicted. In another embodiment, the compound may be atleast 95 the absolute stereoisomer depicted. In another embodiment, thecompound may be at least 99% the absolute stereoisomer depicted.

It is to be understood that the term “and/or an enantiomer thereof”refers to the compound and the enantiomer. For example, the term “acompound of formula Ia or/and an enantiomer thereof”:

refers to both the compound of formula Ia (as shown above) and itsenantiomer (the compound of formula Ib):

Specific embodiments listed below for radicals, substituents, andranges, are for illustration only; they do not exclude other definedembodiments or values or other values within defined ranges for theradicals and substituents. It is to be understood that two or moreembodiments may be combined. Specific embodiments listed below areembodiments for compounds of formula I and formula II as well as allrelated formulas (e.g., compounds of formulas Ia, Ib, Ic, Id, Ia1).

One embodiment provides a compound of formula Ia or a salt thereof or anenantiomer thereof or a salt thereof, or a compound of formula II or anenantiomer thereof:

wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl and each dashed bondis a single bond or double bond provided no two double bonds of thecompound of formula II are cumulated.

One embodiment provides a compound of formula Ia:

or a salt thereof or an enantiomer or a salt thereof, wherein R is H,(C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a compound of formula Ic or Id:

or a salt thereof or an enantiomer or a salt thereof, wherein R is H,(C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.

One embodiment provides a compound of formula Ic or Id:

or an enantiomer thereof, wherein R is H, (C₁-C₆)alkyl, or(C₃-C₆)cycloalkyl.

One embodiment provides a compound of formula II:

or an enantiomer thereof.

One embodiment provides a compound that is:

or a salt thereof.

One embodiment provides a compound that is:

or a salt thereof.

One embodiment provides a compound that is:

or a salt thereof.

One embodiment provides a compound that is:

or a salt thereof.

One embodiment provides a compound that is:

One embodiment provides a composition comprising:

or salts thereof.

One embodiment provides a composition comprising:

Methods for the Preparation of the Compound of Formula Ic1 and theEnantiomer Thereof.

The compound of formula Ic1 and the enantiomer thereof (Ic2), whichcompounds are also shown as compound 14 and the enantiomer thereof, maybe prepared by contacting (i.e., reacting) furfuryl alcohol and itaconicanhydride as described in Example I.

The reaction of furfuryl alcohol and itaconic anhydride can be performedat a variety of temperatures including ambient temperature (roomtemperature such as about 20-25° C.). The reaction can be performed inthe presence or absence of solvent. The ratio of reactants (ratio offurfuryl alcohol to itaconic) can also be varied.

Accordingly, one embodiment provides a method for preparing a compoundof formula Ic1 or a salt thereof or an enantiomer or a salt thereof,comprising converting furfuryl alcohol to the compound of formula Ic1 ora salt thereof or the enantiomer or a salt thereof. Another embodimentprovides a method for preparing a compound of formula Ic1 or a saltthereof or an enantiomer or a salt thereof, comprising convertingitaconic anhydride to the compound of formula Ic1 or a salt thereof orthe enantiomer or a salt thereof. Another embodiment provides a methodfor preparing a compound of formula Ic1 or a salt thereof or anenantiomer or a salt thereof, comprising contacting furfuryl alcoholwith itaconic anhydride to provide the compound of formula Ic1 or a saltthereof or the enantiomer or a salt thereof.

In one embodiment the contacting is done at or about ambienttemperature. In one embodiment the contacting is performed in theabsence of solvent. In one embodiment the ratio of furfuryl alcohol toitaconic anhydride is about 1.5/1 to 2.5/1. In one embodiment the ratioof furfuryl alcohol to itaconic anhydride is about 2/1. One embodimentprovides a method for preparing a composition comprising the compound offormula Ic1 or a salt thereof and the enantiomer of the compound offormula Ic1 or a salt thereof.

One embodiment provides a method for preparing a preparing a compositioncomprising a compound of formula Ic1 and a compound of formula Ic2:

One embodiment provides a compound as provided herein. One embodimentprovides a compound as shown in Scheme 2A.

The compound of formula Ic1 and the enantiomer thereof may be convertedto other compounds that have utility, for example as monomers orintermediates to prepare monomers, which monomers may be used to prepareuseful polymers. Accordingly, certain embodiments provide methods toprepare compounds including but not limited to compounds of formula 17,18, 20, 21, 22, 23, and 24 and enantiomers thereof. Certain compoundsprepared from the compound of formula Ic1 and the enantiomer thereof arenovel. For example, certain embodiments provide a compound of formula17, 20, 21 and 22 and enantiomer thereof.

In one embodiment the invention provides a polymer having a backbonethat comprises one or more groups of the following formula in thebackbone:

wherein:

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—;

each Z is absent or is CH₂; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer that comprises atleast two repeating units of the following formula:

wherein:

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—;

each Z is absent or is CH₂; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer that has thefollowing formula:

wherein:

n is an integer from 3 to 200, inclusive;

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—;

each Z is absent or is CH₂; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer having a backbonethat comprises one or more groups of the following formula in thebackbone:

wherein each R¹ is independently H or methyl; and each Z is absent or isCH₂.

In one embodiment the invention provides a method comprising,polymerizing the compound:

wherein:

R¹ is H or (C₁-C₆) alkyl;

X is absent or is —C(═O)—;

Y is absent or is —C(═O)—;

each Z is absent or is CH₂; and

L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 2 to 10 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by(—O—), and wherein the chain is optionally substituted on carbon withone or more (e.g. 1, 2, 3, or 4) substituents selected from(C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a compound:

wherein:

R¹ is H or (C₁-C₆) alkyl;

X is absent or is —C(═O)—;

Y is absent or is —C(═O)—;

each Z is absent or is CH₂; and

L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 2 to 10 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by(—O—), and wherein the chain is optionally substituted on carbon withone or more (e.g. 1, 2, 3, or 4) substituents selected from(C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer having a backbonethat comprises one or more groups of the following formula in thebackbone:

wherein:

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer that comprises atleast two repeating units of the following formula:

wherein:

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer that has thefollowing formula:

wherein:

n is an integer from 3 to 200, inclusive;

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer having a backbonethat comprises one or more groups of the following formula in thebackbone:

wherein each R¹ is independently H or methyl.

In one embodiment the invention provides a method comprising,polymerizing the compound:

wherein:

R¹ is H or (C₁-C₆) alkyl;

X is absent or is —C(═O)—;

Y is absent or is —C(═O)—; and

L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 2 to 10 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by(—O—), and wherein the chain is optionally substituted on carbon withone or more (e.g. 1, 2, 3, or 4) substituents selected from(C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a compound:

wherein:

R¹ is H or (C₁-C₆) alkyl;

X is absent or is —C(═O)—;

Y is absent or is —C(═O)—; and

L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 2 to 10 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by(—O—), and wherein the chain is optionally substituted on carbon withone or more (e.g. 1, 2, 3, or 4) substituents selected from(C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer having a backbonethat comprises one or more groups of the following formula in thebackbone:

wherein:

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer that comprises atleast two repeating units of the following formula:

wherein:

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer that has thefollowing formula:

wherein:

n is an integer from 3 to 200, inclusive;

each R¹ is independently H or (C₁-C₆) alkyl;

each X is independently absent or is —C(═O)—;

each Y is independently absent or is —C(═O)—; and

each L is independently a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 2 to 10 carbon atoms,wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from (C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a polymer having a backbonethat comprises one or more groups of the following formula in thebackbone:

wherein each R¹ is independently H or methyl.

In one embodiment the invention provides a method comprising,polymerizing the compound:

wherein:

R¹ is H or (C₁-C₆) alkyl;

X is absent or is —C(═O)—;

Y is absent or is —C(═O)—; and

L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 2 to 10 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by(—O—), and wherein the chain is optionally substituted on carbon withone or more (e.g. 1, 2, 3, or 4) substituents selected from(C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment the invention provides a compound:

wherein:

R¹ is H or (C₁-C₆) alkyl;

X is absent or is —C(═O)—;

Y is absent or is —C(═O)—; and

L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 2 to 10 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by(—O—), and wherein the chain is optionally substituted on carbon withone or more (e.g. 1, 2, 3, or 4) substituents selected from(C₁-C₆)alkoxy, halo, and oxo (═O).

In one embodiment n is an integer from 3 to 100, inclusive.

In one embodiment n is an integer from 3 to 50, inclusive.

In one embodiment n is an integer from 3 to 25, inclusive.

In one embodiment each R¹ is independently H or methyl.

In one embodiment each X is —C(═O)—.

In one embodiment each X is absent.

In one embodiment each Y is —C(═O)—.

In one embodiment each Y is absent.

In one embodiment each L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 2 to 10 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—), and wherein the chain is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from halo.

In one embodiment each L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 2 to 10 carbonatoms, wherein one or more of the carbon atoms is replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from halo.

In one embodiment each L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 2 to 5 carbonatoms, wherein one or more of the carbon atoms is replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from halo.

In one embodiment each L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 2 to 5 carbonatoms, wherein one or more of the carbon atoms is optionally replaced by(—O).

In one embodiment each L is —O—CH₂—CH₂—O—.

The compound of formula III may be polymerized to provide organic-basedpolymers. Since these polymers are derived from the compound of formulaIII they are ultimately sourced from renewable resources. The compoundof formula III may be polymerized by ring-opening metathesispolymerization (ROMP) with an appropriate catalyst (e.g., a Grubb'scatalyst such as a Grubb's III catalyst) to provide a polymer comprisingresidues of formula 26a:

wherein: m is 1 or 2; and R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl; ora salt thereof. In one embodiment the residues of formula 26a areselected from:

The compound of formula I (e.g., formula Ic1 and the enantiomer thereof)may be polymerized to provide organic-based polymers. Since thesepolymers are derived from the compound of formula I (e.g., formula Ic1and the enantiomer thereof) they are ultimately sourced from renewableresources. The compound of formula I (e.g., formula Ic1 and theenantiomer thereof) may be polymerized by ring-opening metathesispolymerization (ROMP) with an appropriate catalyst (e.g., a Grubb'scatalyst such as a Grubb's III catalyst) to provide a polymer comprisingresidues of formula 26:

wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl; or a salt thereof.In one embodiment the residues of formula 26 are selected from:

In one embodiment the polymer comprises about 10 or more residues offormula 26 or 26a. In one embodiment the polymer comprises about 50 ormore residues of formula 26 or 26a. In one embodiment the polymercomprises about 100 or more residues of formula 26 or 26a. In oneembodiment the polymer comprises about 1000 or more residues of formula26 or 26a. In one embodiment the polymer comprises about 2 or morerepeating residues of formula 26 or 26a. In one embodiment the polymercomprises about 5 or more repeating residues of formula 26 or 26a. Inone embodiment the polymerization includes an initiator diene (e.g.,diethyl diallylmalonate) to promote the polymerization. In oneembodiment R is (C₁-C₆)alkyl. In one embodiment R is methyl. In oneembodiment the residues of formula 26 or 26a form the backbone of thepolymer.

In cases where compounds are sufficiently acidic, a salt of a compoundof formula I can be useful as an intermediate for isolating or purifyinga compound of formula I. Additionally, administration of a compound offormula I as a pharmaceutically acceptable acid or base salt may beappropriate. Examples of pharmaceutically acceptable salts includeorganic acid addition salts formed with acids that form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic acidaddition salts may also be formed, that include a physiologicalacceptable anion, for example, chloride, sulfate, nitrate, bicarbonate,and carbonate salts.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1 A. General Experimental Protocols

¹H and ¹³C NMR spectra were recorded on a Bruker Avance III or Avance II500 (500 MHz), a Bruker Avance III 400 (400 MHz), or Varian VXR 300 (300MHz) spectrometer. ¹H NMR chemical shifts in CDCl₃, C₆D₆, or CD₃OD arereferenced to TMS (0.00 ppm), C₆HD₅ (7.16 ppm), or CHD₂OD (3.31 ppm),respectively. A non-first order multiplet is designated as “nfom”. ¹³CNMR chemical shifts are referenced to chloroform CDCl₃ at 77.16 ppm orbenzene C₆D₆, at 128.06 ppm. Proton resonances are reported using thefollowing format: chemical shift in ppm (multiplicity, couplingconstants (J) in Hz, integral value to the nearest whole proton, andassignment). Coupling constant analysis followed protocols previouslyreported (Hoye, T. R., et al., J Org. Chem. 1994, 59, 4096-4103; Hoye,T. R., Zhao, H. J. Org. Chem. 2002, 67, 4014-4016).

Infrared (IR) spectra were recorded as solid samples on a Bruker AlphaPlatinum spectrometer using attenuated total reflectance (ATR) sampling.The wavenumber of absorption bands are reported in cm⁻¹.

Medium pressure liquid chromatography (MPLC, 50-100 psi) was carried outon hand-packed silica gel (25-35 μm, 60 Å pores) columns. A Waters HPLCpump outfitted with a Waters R401 differential refractive index detectorand a Gilson UV detector was used. Flash chromatography was performed onsilica gel columns (E. Merck, 40-63 μm).

Mass spectrometry data were collected on: i) an Agilent 5973 GC-MSinstrument with electron impact ionization (at 70 eV) or ii) a BrukerBioTOF II instrument using electrospray ionization and a PEG internalcalibrant for HRMS measurements, or iii) a Bruker Biflex III instrumentto carry out the matrix-assisted laser desorption ionizationtime-of-flight mass spectroscopy (MALDI-ToF-MS), using2,5-dihydroxybenzoic acid as the matrix.

Size exclusion chromatography (SEC) measurements were performed on anAgilent 1100 series liquid chromatograph equipped with a Varian PLgel 5mm guard column three Varian Plgel mixed C columns. Analyses wereperformed at 35° C. with chloroform as the mobile phase. A flow rate of1 mL·min⁻¹ was used and effluent peaks were detected with a differentialrefractive index detector (HP1047A). Molar masses were determined usinga 10-point calibration curve, established using polystyrene standardsobtained from Polymer Laboratories.

Differential scanning calorimetry (DSC) was carried out on a DiscoveryDSC instrument manufactured by TA Instruments. Samples were initiallyheated to 240° C. and equilibrated at that temperature for 5 min, cooledto −20° C., and ramped back to 240° C. at 10° C. per min. Data wereanalyzed using Trios Software from TA Instruments.

B. Preparation, Procedures and Characterization Data for CompoundsPreparation of(±)-(1R,2S,4R)-2′H-7-oxaspiro[bicyclo[2.2.1]heptane-2,3′-furan]-5-ene-2′,5′(4′H)-dione(4-endo) and(±)-(1R,2R,4R)-2′H-7-oxaspiro[bicyclo[2.2.1]heptane-2,3′-furan]-5-ene-2′,5′(4′H)-dione(4-exo)

Itaconic anhydride (1, 164 mg, 1.46 mmol) was added to furan (3, 110 μL,1.47 mmol). The resulting suspension was stirred at ambient temperaturefor 48 h. The reaction mixture never became homogenous. An aliquot ofthe mixture was dissolved in CDCl₃ and quickly analyzed by ¹H NMRspectroscopy, which indicated ca. 60% of each of 1 and 3 along with ca.40% of a combined mixture of the two isomeric adducts 4-endo and 4-exo.The material was purified by MPLC on silica gel (3:1 hexanes:EtOAcelution) to provide, in order of elution, 4-endo (26.4 mg, 0.147 mmol,10%) followed by 4-exo (39.6 mg, 0.22 mmol, 15%).

Data for 4-Endo:

¹H NMR (CDCl₃, 500 MHz) δ 6.66 (dd, J=5.9, 1.7 Hz, 1H), 6.36 (dd, J=5.9,1.5 Hz, 1H), 5.20 (nfom, 1H, H4), 4.83 (dd, J=1.8, 1.0 Hz, 1H, H1), 3.20(d, J=19.1 Hz, 1H, C4′H_(a)H_(b)), 3.08 (d, J=19.1 Hz, 1H,C4′H_(a)H_(b)), 2.07 (dd, J=11.6, 3.6 Hz, 1H, C3H_(a)H_(b)), and 2.05(ddd, J=11.7, 4.8, 1.2 Hz, 1H, C3H_(a)H_(b)).

¹H NMR (C₆D₆, 500 MHz) δ 5.95 (dd, J=5.8, 1.4 Hz, 1H), 5.80 (dd, J=5.8,1.0 Hz, 1H), 4.32 (br d, J=4.3 Hz, 1H, H4), 3.68 (br s, 1H, H1), 2.29(d, J=18.9 Hz, 1H, C4′H_(a)H_(b)), 1.90 (d, J=18.9 Hz, 1H,C4′H_(a)H_(b)), 1.24 (d, J=11.6 Hz, 1H, C3H_(a)H_(b)), and 0.91 (dd,J=11.6, 4.5 Hz, 1H, C3H_(a)H_(b)).

¹³C NMR (C₆D₆, 125 MHz) δ 173.1, 169.0, 137.9, 132.1, 85.9, 79.5, 49.3,41.9, and 41.2.

IR (neat): 3014, 2961, 1845, 1767, 1697, 1307, 1238, 987, and 874 cm⁻¹.

mp: 102-104° C.

Data for 4-Exo:

¹H NMR (CDCl₃, 500 MHz) δ6.71 (dd, J=5.8, 1.7 Hz, 1H), 6.48 (dd, J=5.8,1.5 Hz, 1H), 5.26 (d, J=4.3 Hz, 1H, H4), 5.11 (s, 1H, H1), 2.77 (d,J=19.3 Hz, 1H, C4′H_(a)H_(b)), 2.76 (d, J=19.3 Hz, 1H, C4′H_(a)H_(b)),2.71 (dd, J=11.5, 4.7 Hz, 1H, C3H_(exo)H_(endo)), and 1.53 (d, J=11.5Hz, 1H, C3H_(exo)H_(endo)).

¹H NMR (C₆D₆, 500 MHz) δ 5.67 (dd, J=5.8, 1.7 Hz, 1H), 5.38 (dd, J=5.8,1.6 Hz, 1H), 4.44 (dd, J=4.7, 1.6 Hz, 1H, H4), 4.17 (s, 1H, H1), 2.00(dd, J=11.5, 4.7 Hz, 1H, C3H_(exo)H_(endo)), 1.61 (d, J=18.9 Hz, 1H,C4′H_(a)H_(b)), 1.52 (d, J=19.0 Hz, 1H, C4′H_(a)H_(b)), and 0.30 (dd,J=11.5 Hz, 1H, C3H_(exo)H_(endo)).

¹³C NMR (C₆D₆, 125 MHz) δ 174.6, 169.0, 139.5, 133.2, 82.5, 79.1, 49.0,40.8, and 37.7.

IR (neat): 3032, 2947, 1839, 1769, 1229, 1097, 971, 921, 698, 434 cm⁻¹.

mp: 159-162° C.

Preparation of(±)-(1R,2S,4S)-2′H-7-oxaspiro[bicyclo[2.2.1]heptane-2,3′-furan]-2′,5′(4′H)-dione(4-endo-h2) and(±)-(1R,2R,4S)-2′H-7-oxaspiro[bicyclo[2.2.1]heptane-2,3′-furan]-2′,5′(4′H)-dione(4-exo-h2)

Acetone (100 mL) was placed in a 250 mL, two-neck, round-bottom flask.10% Pd/C (600 mg) was added. The homogeneous mixture of DA-adducts4-endo and 4-exo described in the preceding procedure (6.0 g, 33.3 mmol)was added, and the reaction flask headspace was immediately sparged withH₂. This suspension was stirred for 3 h and then filtered through a padof Celite®, that was washed thoroughly with acetone (20 mL). Thefiltrate was concentrated in vacuo to provide an off-white solid, thatwas dried overnight under vacuum to give the crude mixture of products4-endo-h2 and 4-exo-h2 (along with some methylsuccinic anhydrideresulting from reduction of the portion of itaconic anhydride in thereactant mixture). A portion of this material (ca. 200 mg) was purifiedby MPLC on silica gel (5:1 hexanes:EtOAc elution) to provide, in orderof elution, 4-endo-h2 (26.4 mg, 0.147 mmol, 10%) followed by 4-exo-h2(39.6 mg, 0.22 mmol, 15%).

Data for 4-Endo-h2:

¹H NMR (CDCl₃, 500 MHz) δ 4.76 (dd, J=5.3, 5.3 Hz, 1H, H4), 4.43 (d,J=5.0 Hz, 1H, H1), 3.22 (d, J=18.9 Hz, 1H, C4′H_(a)H_(b)), 2.76 (d,J=19.0 Hz, 1H, C4′H_(a)H_(b)), 2.26 (d, J=12.5 Hz, 1H,C3H_(endo)H_(exo)), 2.14 (ddd, J=12.7, 9.0, 4.3 Hz, 1H, H6_(endo)), 1.92(ddd, J=12.4, 5.4, 2.7 Hz, 1H, H3_(exo)), 1.86-1.78 (nfom, 1H,H5_(exo)), and 1.73-1.65 (m, 2H, H6_(exo) and H5_(endo)).

¹H NMR (C₆D₆, 500 MHz) δ 4.00 (dd, J=5.3, 5.3 Hz, 1H, H4), 3.31 (d,J=5.2 Hz, 1H, H1), 2.37 (d, J=18.7 Hz, 1H, C4′H_(a)H_(b)), 1.77 (ddd,J=12.7, 9.0, 4.3 Hz, 1H, H6_(endo)), 1.55 (d, J=18.7 Hz, 1H,C4′H_(a)H_(b)), 1.52 (d, J=12.5 Hz, 1H, C3H_(endo)H_(exo)), 1.28 (ddddd,J=12.1, 12.1, 4.7, 4.7, 2.6 Hz, 1H, H5exo), 1.18 (ddd, J=11.7, 9.1, 4.6Hz, 1H, H5_(endo)), 1.07 (dddd, J=12.6, 12.6, 4.9, 4.9 Hz, 1H,H6_(exo)), and 0.85 (ddd, J=12.5, 5.4, 2.7 Hz, 1H, H3_(exo)).

¹³C NMR (C₆D₆, 125 MHz) δ 173.7, 168.7, 84.4, 77.8, 54.3, 43.9, 43.9,29.3, and 24.8.

IR (neat): 1843, 1762, 1237, 1104, 965, 872, and 460 cm⁻¹. mp: 149-153°C.

HRMS (ESI-TOF): Calcd for C₁₀H₁₄NaO₅ ⁺ [M+MeOH+Na⁺] requires 237.0733;found 233.0725.

Data for 4-Exo-h2:

¹H NMR (500 MHz, CDCl₃) δ 4.79 (dd, J=5.1, 5.1 Hz, 1H, H4), 4.73 (d,J=4.6 Hz, 1H, H1), 3.09 (d, J=18.7 Hz, 1H, C4′H_(a)H_(b)), 3.02 (d,J=18.8 Hz, 1H, C4′H_(a)H_(b)), 2.50 (ddd, J=12.3, 5.4, 1.9 Hz, 1H,H3_(exo)), 1.93-1.84 (m, 2H), 1.84-1.75 (nfom, 1H, H6_(endo)), 1.63 (d,J=12.3 Hz, 1H, H3_(endo)), and 1.60-1.52 (nfom, 1H, H5_(endo)).

¹H NMR (C₆D₆, 500 MHz) δ 4.12 (dd, J=4.1, 4.1 Hz, 1H, H4), 3.92 (d,J=5.2 Hz, 1H, H1), 1.86 (d, J=18.5 Hz, 1H, C4′H_(a)H_(b)), 1.86 (ddd,J=12.3, 5.4, 2.7 Hz, 1H, H3_(exo)), 1.77 (d, J=18.5 Hz, 1H,C4′H_(a)H_(b)), 1.22 (ddddd, J=12.1, 12.1, 5.4, 3.9, 2.8 Hz, 1H,H5_(exo)), 1.09 (dddd, J=12.7, 12.7, 4.9, 4.9 Hz, 1H, H6exo), 0.75 (ddd,J=12.8, 9.0, 3.9 Hz, 1H, H6_(endo)), 0.62 (ddd, J=11.8, 9.3, 4.9 Hz, 1H,H5_(endo)), and 0.47 (d, J=12.3 Hz, 1H, H3_(endo)).

¹³C NMR (C₆D₆, 125 MHz) δ 174.2, 169.0, 80.8, 76.9, 52.3, 43.7, 36.8,29.0, and 26.3.

IR (neat): 3007, 2975, 2949, 2875, 1843, 1762, 1455, 1307, 1237, 1104,965, and 873 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₄NaO₅ ⁺ [M+MeOH+Na⁺] requires 237.0733;found 233.0740.

mp: 156-158° C.

Preparation of(±)-(1R,2S,4S)-2-(carboxymethyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylicacid (5)

Anhydride 4-endo-h2 (4 mg) was suspended in deionized water (1 mL) in a10 mL culture tube. The reaction mixture was heated to 110° C. to give aclear solution that was stirred for 3 hours.

The solution was cooled to room temperature and extracted with 4 mL ofethyl acetate. The organic layer was dried over anhydrous MgSO₄ andconcentrated in vacuo to give the diacid 5 as a white solid (3.5 mg,81%).

¹H NMR (500 MHz, acetone-d₆) δ 11.12-10.60 (br s, 2H, CO₂H), 4.56 (dd,J=5.2, 5.2 Hz, 1H, H4), 4.25 (d, J=4.7 Hz, 1H, H1), 3.05 (d, J=16.5 Hz,1H, C4′H_(a)H_(b)), 2.60 (d, J=16.5 Hz, 1H, C4′H_(a)H_(b)), 2.31 (d,J=12.5 Hz, 1H, C3H_(endo)H_(exo)), 1.72-1.65 (m, 1H), 1.65-1.59 (m, 1H),1.59-1.54 (m, 2H), and 1.54-1.48 (m, 1H).

¹³C NMR (125 MHz, acetone-d₆) δ 174.9, 172.8, 82.8, 79.0, 56.0, 43.7,41.2, 29.8, and 26.9.

IR (neat): 3300-2500 (br), 2997, 2990, 2974, 1727, 1692, 1411, 1255,1190, 1145, 1039, 980, 913, 859, and 821 cm⁻¹

HRMS (ESI-TOF): Calcd for C₉H₁₂NaO₅ ⁺ [M+Na⁺] requires 233.0577; found233.0573.

mp: 170-173° C.

Isolation of anhydrides (12-dist)(±)-(1S,2R,4S)-4-(hydroxymethyl)-2′H-7-oxaspiro-[bicyclo[2.2.1]heptane-2,3′-furan]-5-ene-2′,5′(4′H)-dione(12-dist-endo) and(±)-(1S,2S,4S)-4-(hydroxymethyl)-2′H-7-oxaspiro[bicyclo[2.2.1]heptane-2,3′-furan]-5-ene-2′,5′(4′H)-dione(12-dist-exo)

Itaconic anhydride (1, 3.0 g, 26.7 mmol) was suspended in furfurylalcohol (2, 2.3 mL, 2.6 g, 26.7 mmol) and this slurry was allowed tostir (magnetically) at ambient temperature. After ca. 10 minutes, aportion (200 mg) of the mixture was purified by MPLC (hexanes:EtOAc 3:1)to give the anhydrides 12-dist-endo (1 mg, 0.5%) and 12-dist-exo (1 mg,0.5%), each as a white solid.

The chromatographic effluent and NMR sample solutions of these compoundswere handled and analyzed quickly, because they were susceptible toreversion back to 1 and 2. (also, see following procedure for isolationof 12-prox-endo and 13.)

Data for 12-Dist-Endo:

¹H NMR (500 MHz, CDCl₃) δ 6.59 (d, J=5.8 Hz, 1H, H5), 6.42 (dd, J=5.8,1.3 Hz, 1H, H6), 4.84 (d, J=1.5 Hz, 1H, H1), 4.18 (d, J=12.5 Hz, 1H,CH_(a)H_(b)OH), 4.05 (d, J=12.6 Hz, 1H, CH_(a)H_(b)OH), 3.22 (d, J=19.1Hz, 1H, C4′H_(a)), 3.12 (d, J=19.1 Hz, 1H, C4′H_(b)), 2.08 (d, J=11.5Hz, 1H, C3H_(a)), 2.02 (d, J=11.5 Hz, 1H, C3H_(b)), and 1.78 (br s, 1H,OH).

Data for 12-Dist-Exo:

¹H NMR (500 MHz, CDCl₃) δ 6.67 (d, J=5.8 Hz, 1H, H5), 6.54 (dd, J=5.8,1.4 Hz, 1H, H6), 5.11 (d, J=1.6 Hz, 1H, H1), 4.18 (d, J=12.6 Hz, 1H,CH_(a)H_(b)OH), 4.11 (d, J=12.6 Hz, 1H, CH_(a)H_(b)OH), 2.79 (s, 2H,H4′), 2.62 (d, J=11.5 Hz, 1H, C3H_(a)), 1.95 (br s, 1H, OH), and 1.55(d, J=11.5 Hz, 1H, C3H_(b)).

Isolation of lactone acid(±)-(4aS,6R,8aR)-3-oxo-3,4,5,6-tetrahydro-1H,4aH-6,8a-epoxyisochromene-4a-carboxylicacid (13)

Itaconic anhydride (1, 3.0 g, 26.7 mmol) was suspended in furfurylalcohol (2, 2.3 mL, 2.6 g, 26.7 mmol) and this slurry was allowed tostir (magnetically) at ambient temperature. After approximately 10minutes, a portion (200 mg) of the mixture was purified by MPLC(hexanes:EtOAc 3:1) to give a fraction containing, principally,12-prox-endo and 13. Upon standing, the 12-prox-endo in a CDCl₃ solutionof this mixture was observed to fully convert to the 6-membered lactoneacid 13 (see copy of ¹H NMR spectrum for 12-prox-endo), that was thenobtained as white solid (1 mg, 0.5%). (also, see previous procedure forisolation of 12-dist-endo and 12-dist-exo.)

Data for 13:

¹H NMR (500 MHz, acetone-d₆) δ 6.64 (dd, J=5.7, 1.7 Hz, 1H, H7), 6.21(d, J=5.7 Hz, 1H, H8), 5.12 (d, J=13.2 Hz, 1H, H1a), 5.06 (dd, J=4.8,1.6 Hz, 1H, H6), 4.69 (d, J=13.2 Hz, 1H, H1b), 3.03 (d, J=16.8 Hz, 1H,C4H_(a)H_(b)), 2.70 (d, J=16.8 Hz, 1H, C4H_(a)H_(b)), 2.15 (d, J=11.8Hz, 1H, H5endo), and 1.96 (dd, J=11.8, 4.8 Hz, 1H, H5exo). ¹³C NMR (125MHz, CDCl₃) δ 176.8, 168.6, 140.3, 132.4, 84.6, 79.2, 68.5, 50.5, 39.9,and 39.5.

IR (neat): 3300-2700 (br s), 3088, 2951, 1715, 1696, 1454, 1423, 1311,1262, 1184, 1016, 954, and 853 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₀NaO₅ ⁺ [M+Na⁺] requires 233.0420; found233.0422.

mp: 116-121° C.

Data for 12-Prox-Endo

¹H NMR (500 MHz, CDCl₃) δ 6.66 (br d, J=5.6 Hz, 1H, H5), 6.44 (d, J=5.8Hz, 1H, H6), 5.13 (dd, J=4.5, 1.7 Hz, 1H, H4), 4.20 (d, J=10.9 Hz, 1H,CH_(a)H_(b)OH), 4.07 (d, J=10.9 Hz, 1H, CH_(a)H_(b)OH), 3.40 (d, J=19.1Hz, 1H, C4′H_(a)), 2.93 (d, J=19.1 Hz, 1H, C4′H_(b)), 2.22 (d, J=11.6Hz, 1H, C3H_(endo)), and 2.14 (dd, J=11.6, 4.6 Hz, 1H, C3H_(exo)).

Preparation of methyl(±)-(4aS,6R,8aR)-3-oxo-3,4,5,6-tetrahydro-1H,4aH-6,8a-epoxyisochromene-4a-carboxylate(13^(Me))

Lactone acid 13 (1 mg) was dissolved in a 1:1 mixture of MeOH andtoluene (1 mL) in a 5 mL vial. Excess TMSCHN₂ (2 drops) was added to thesolution, and the top portion of the solution turned yellow. The vialwas capped and gently shaken and allowed to stand for 30 minutes. Thereaction mixture was then concentrated in vacuo to give 13^(Me) as anoff-white solid (1 mg).

¹H NMR (400 MHz, CDCl₃) δ 6.61 (dd, J=5.7, 1.8 Hz, 1H, H7), 6.06 (d,J=5.7 Hz, 1H, H8), 5.13-5.02 (m, 2H, H6 and C1H_(a)H_(b)), 4.81 (d,J=13.3 Hz, 1H, C1H_(a)H_(b)), 3.71 (s, 3H, CO₂CH₃), 3.05 (d, J=16.8 Hz,1H, C4H_(a)H_(b)), 2.74 (d, J=16.8 Hz, 1H, C4H_(a)H_(b)), 2.20 (d,J=12.0 Hz, 1H, H5_(endo)), and 1.97 (dd, J=12.0, 4.7 Hz, 1H, H5_(exo)).

Preparation of(±)-2-((3aR,6R,7aR)-1-oxo-6,7-dihydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetic acid (14)

Method A:

Itaconic anhydride (1, 3.0 g, 26.7 mmol) was suspended in furfurylalcohol (2, 2.3 mL, 2.6 g, 26.7 mmol) and this slurry was allowed tostir (magnetically) at ambient temperature. After approximately fivehours, the suspension had thickened to a paste and could no longer bestirred. After approximately 12 hours, this mixture had turned to asolid light brown mass. The lactone 14 could be stored indefinitely as atan crystalline solid.

Method B:

Itaconic anhydride (1, 1.5 g, 13.3 mmol) was added to furfuryl alcohol(2, 2.3 mL, 2.6 g, 26.7 mmol). This slurry was allowed to stir(magnetically) at ambient temperature and it turned into a clearsolution in 30 minutes. After five hours, lactone acid 14 began toprecipitate from this solution. After 48 hours the slurry was filteredand the solid was washed with 5 mL of dichloromethane to give 14 as awhite solid (1.97 g, 70%).

¹H NMR (500 MHz, CDCl₃, sparingly soluble) δ 6.59 (dd, J=5.8, 1.7 Hz,1H, H15), 6.49 (d, J=5.8 Hz, 1H, H4), 5.06 (dd, J=4.7, 1.6 Hz, 1H, H6),4.83 (d, J=10.8 Hz, 1H, C3H_(a)H_(b)), 4.64 (d, J=10.8 Hz, 1H,C3H_(a)H_(b)), 2.58 (dd, J=12.3, 4.7 Hz, 1H, C7H_(endo)H_(exo)), 2.54(d, J=15.1 Hz, 1H, C8H_(a)H_(b)), 2.40 (d, J=15.1 Hz, 1H, C8H_(a)H_(b)),and 1.52 (d, J=12.3 Hz, 1H, C7H_(endo)H_(exo)).

¹H NMR (500 MHz, acetone-d₆) δ 6.62 (dd, J=5.8, 1.5 Hz, 1H, H5), 6.59(d, J=5.8 Hz, 1H, H4), 5.03 (dd, J=4.7, 1.3 Hz, 1H, H6), 4.94 (d, J=10.8Hz, 1H, C3H_(a)H_(b)), 4.51 (d, J=10.8 Hz, 1H, C3H_(a)H_(b)), 2.44 (d,J=15.0 Hz, 1H, C8H_(a)H_(b)), 2.39 (d, J=15.0 Hz, 1H, C8H_(a)H_(b)),2.35 (dd, J=12.2, 4.8 Hz, 1H, C7H_(exo)H_(endo)), and 1.58 (d, J=12.2Hz, 1H, C7H_(exo)H_(endo)). ¹³C NMR (125 MHz, acetone-d₆) δ 177.8,171.2, 139.0, 131.5, 95.1, 79.6, 69.1, 52.6, 40.2, and 37.4.

IR (neat): 3300-2500 (br), 2994, 1705, 1397, 1324, 1154, 974, 709, and646 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₉O₅ [M−1⁻] requires 209.0455; found209.0453.

mp: 137-139° C.

Preparation of (±)-methyl2-((3aR,6R,7aR)-1-oxo-6,7-dihydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetate (14^(Me))

Lactone acid (14, 2.78 g, 13.2 mmol) was dissolved in methanol (10 mL)in a 50 mL two-neck round-bottom flask. Sulfuric acid (0.20 mL, 3.8mmol) was added. The solution immediately turned deep brown. Thissolution was stirred overnight at room temperature and the color turneddarker. The reaction mixture was concentrated in vacuo and the residuewas purified by flash column chromatography on silica gel (CH₂Cl₂elution) to give lactone ester 14^(Me) (2.30 g, 10.3 mmol, 80%) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ 6.54 (d, J=5.8 Hz, 1H, H5), 6.48 (d, J=5.8 Hz,1H, H4), 5.03 (d, J=4.7 Hz, 1H, H6), 4.78 (d, J=10.8 Hz, 1H,C3H_(a)H_(b)), 4.59 (d, J=10.8 Hz, 1H, C3H_(a)H_(b)), 3.67 (s, 3H,OCH₃), 2.53 (d, J=11.4 Hz, 1H, C7H_(endo)H_(exo)), 2.10 (d, J=14.6 Hz,1H, C8H_(a)H_(b)), 2.31 (d, J=14.6 Hz, 1H, C8H_(a)H_(b)), and 1.48 (d,J=12.2 Hz, 1H, C7H_(endo)H_(exo)).

¹³C NMR (125 MHz, CDCl₃) δ 177.2, 170.0, 138.2, 130.7, 94.1, 78.8, 68.8,52.3, 52.1, 39.9, and 36.8.

IR (neat): 1767, 1723, 1437, 1320, 1523, 1178, 1129, 1047, 988, 850, and707 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₁H₁₂NaO₅ ⁺ [M+Na^(+]) requires 247.0577;found 247.0583.

mp: 126-129° C.

Preparation of 1-(furan-2-ylmethyl) 4-methyl 2-methylenesuccinate(15a^(Me))

Method A:

A mixture of (commercial) mono-methyl itaconate 16 (1.0 g, 6.9 mmol),triphenylphosphine (2.6 g, 10.0 mmol), and furfuryl alcohol (0.6 mL, 6.9mmol) was dissolved in 20 mL of CH₂Cl₂. The solution was gently stirredfor 10 min at room temperature. Diethyl azodicarboxylate (DEA, 1.5 mL,10.2 mmol) was added to the reaction mixture, that was then stirred atroom temperature for 17 h. The reaction mass was filtered and thefiltrate concentrated. The residue was purified by flash columnchromatography on SiO₂ (hexanes/EtOAc, 3:1) to give 15a^(Me) (1.9 g,85%) as a colorless oil.

Method B:

A neat sample of the lactone methyl ester 14^(Me) (200 mg, 0.89 mmol)was placed in a vial and heated to 140° C. for 20 min. The vial wasallowed to cool to room temperature to leave a black oil. This residuewas purified by flash column chromatography on SiO₂ (hexanes/EtOAc, 3:1)to give 15a^(Me) as a colorless oil (153 mg, 75%).

¹H NMR (500 MHz, CDCl₃) δ 7.41 (dd, J=1.7, 0.7 Hz, 1H, H5′), 6.42 (d,J=3.2 Hz, 1H, H3′), 6.36-6.35 (m, 2H, H4′ and ═CH_(Z)H_(E)), 5.72 (br s,1H, ═CH_(Z)H_(E)), 5.15 (s, 2H, furanylCH₂O), 3.66 (s, 3H, CH₃O), and3.34 (dd, J=1.1, 1.1 Hz, 2H, C3H₂).

¹³C NMR (125 MHz, CDCl₃) δ 171.2, 165.9, 149.4, 143.4, 133.6, 129.3,110.9, 110.7, 58.8, 52.2, and 37.7.

IR (neat): 2955, 1717, 1637, 1422, 1289, 1152, 1014, 814, and 749 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₁H₁₂NaO₅ ⁺ [M+Na⁺] requires 247.0582; found247.0575.

TLC: R_(f) 0.52 (5:1 Hex/EtOAc).

Preparation of 4-(furan-2-ylmethoxy)-2-methylene-4-oxobutanoic acid(15b)

A mixture of itaconic anhydride (1, 200 mg, 1.7 mmol) and furfurylalcohol (2, 175 mg, 1.7 mmol) was dissolved in 4 mL of CDCl₃ in around-bottom flask. The solution was heated to 80° C. and stirred for 2h. The reaction mass was concentrated and purified by flash columnchromatography (SiO₂, hexanes/EtOAc, 3:1) to give 15b (0.12 g, 40%) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ 7.42 (d, J=1.7 Hz, 1H, H5′), 6.47 (s, 1H,═CH_(Z)H_(E)), 6.41 (d, J=3.2 Hz, 1H, H3′), 6.36 (dd, J=3.2, 1.9 Hz, 1H,H4′), 5.83 (s, 1H, ═CH_(Z)H_(E)), 5.11 (s, 2H, CH₂O), and 3.37 [s, 2H,(HOOC)C(═CH₂)CH₂].

¹³C NMR (125 MHz, CDCl₃) δ 171.0, 170.4, 149.3, 143.5, 133.1, 131.1,111.0, 110.8, 58.8, and 37.3.

IR (neat): 3300-2500 (br), 3116, 2968, 2903, 2751, 1735, 1695, 1635,1321, 1168, 1152, 930, 915, and 744 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₀NaO₅ ⁺ [M+Na⁺] requires 233.0420; found233.0418.

mp: 67-69° C.

Preparation of 4-(furan-2-ylmethyl) 1-methyl 2-methylenesuccinate(15b^(Me))

Method A:

Mono-ester acid 15b (1 mg) was dissolved in an equivolume mixture ofMeOH and toluene (1 mL) in a 5 mL vial. Excess TMSCHN₂ (2 drops) wasadded to the solution, and the top portion of the solution turnedyellow. The vial was capped, gently shaken, and allowed to stand for 30minutes. The reaction mixture was then concentrated in vacuo to give15b^(Me) as an off-white solid (1 mg).

Method B:

A neat sample of the lactone methyl ester 13^(Me) (1 mg) was placed in avial and heated in a 140° C. heating bath for 5 min. The vial wasallowed to cool to room temperature to give 15a^(Me) as a brown solid (1mg).

¹H NMR (500 MHz, CDCl₃) δ 7.42 (d, J=1.8 Hz, 1H, H5′), 6.41 (d, J=3.2Hz, 1H, H3′), 6.36 (dd, J=3.1, 1.9 Hz, 1H, H4′), 6.33 (s, 1H,═CH_(Z)H_(E)), 5.71 (s, 1H, ═CH_(Z)H_(E)), 5.09 (s, 2H, CH₂O), 3.74 (s,3H, COOMe), and 3.35 (s, 2H, ═C(CO₂Me)CH₂).

Preparation of (±)-3a,7a-(methanoxymethano)benzofuran-2,10(3H)-dione(17)

Lactone acid 14 (200 mg, 0.95 mmol) was suspended in chloroform (10 mL)in a 50 mL, two-neck, round-bottom flask. Trifluoromethanesulfonic acid(TfOH, 37 μL, 0.47 mmol) was added to the mixture. A brown-black colorwas immediately observed. This solution was stirred for 30 min at 80° C.The color of the solution turned dark brown and formation of a blackprecipitate was observed. The chloroform supernatant was decanted andthe black residue was washed with 10 mL of additional chloroform. Thecombined chloroform layers were concentrated in vacuo and the residuewas purified by flash column chromatography on SiO₂ (3:1 hexanes:EtOAcelution) to give the rearranged dilactone 17 (73 mg, 0.38 mmol, 40%) asa white crystalline solid.

¹H NMR (500 MHz, CDCl₃) δ 6.19-6.11 (nfom, 2H), 6.01-5.91 (nfom, 2H),4.75 (d, J 10.8 Hz, 1H, C8H_(a)H_(b)), 4.25 (d, J=10.8 Hz, 1H,C8H_(a)H_(b)), 3.16 (d, J=18.1 Hz, 1H, C3H_(a)H_(b)), and 2.75 (d,J=18.1 Hz, 1H, C3H_(a)H_(b)).

¹³C NMR (125 MHz, CDCl₃) δ 176.6, 171.8, 125.2, 124.0, 123.3, 123.0,87.5, 76.2, 51.1, and 38.7.

IR (neat): 3150, 3050, 2950, 2900, 1770, 1417, 1361, 1246, 1209, 1186,1040, 1005, 946, 769, and 715 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₈NaO₄ ⁺ [M+Na⁺] requires 215.0315; found215.0325.

TLC: R_(f)0.42 (3:1 Hex/EtOAc).

mp: 105-107° C.

Preparation of 3-isochromanone (18)

Method A:

Lactone acid 14 (1.0 g, 4.7 mmol) was suspended in chloroform-d (10 mL)in a 50 mL two-neck round-bottom flask. Trifluoromethanesulfonic acid(TfOH, 37 μL, 10 mol %) was added. A brown-black color was immediatelyobserved. This solution was stirred overnight at room temp or heated to80° C. at which time the color had become somewhat darker and a blacksolid material had precipitated. The chloroform supernatant was decantedand the black residue was washed with a portion of fresh chloroform. Thecombined chloroform layers were concentrated in vacuo and the residuewas purified by flash column chromatography on SiO₂ (hexanes/EtOAc, 3:1)to give 3-isochromanone 18 (0.45 g, 65%) as white crystalline solid.

Method B:

The lactone methyl ester 14^(Me) (0.5 g, 2.2 mmol) was dissolved inchloroform-d (10 mL) in a 50 mL two-neck round-bottom flask.Trifluoromethanesulfonic acid (TfOH, 20 μL, 10 mol %) was added. Abrown-black color was immediately observed. This solution was stirred at80° C. for 2 hours, at which time the color had become somewhat darker.The chloroform was concentrated in vacuo and the residue was purified byflash column chromatography on SiO₂ (hexanes/EtOAc, 3:1) to give the3-isochromanone 18 (0.23 g, 70%) as a white crystalline solid.

¹H NMR (500 MHz, CDCl₃) δ 7.44-7.21 (m, 4H), 5.40 (s, 2H, CH₂O), and3.79 (s, 2H, CH₂CO).

mp: 80-83 (lit. 80-81° C.; Li T., et al., Helv. Chim. Acta 2014, 97,854)

Preparation of(±)-2-((3aR,6S,7aR)-1-Oxotetrahydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)aceticacid (19)

Acetone (100 mL) was placed in a 250 mL two-neck round-bottom flask.Lactone acid 14 (1.0 g, 4.7 mmol) was added and stirred for 10 minutes.Pd/C (5%, 50 mg) was added and the reaction flask headspace wasimmediately sparged with H₂. The mixture was stirred for 3 h and thenfiltered through a pad of Celite®, that was washed thoroughly withacetone (20 mL). The filtrate was concentrated in vacuo to provide anoff-white solid, that was dried overnight under vacuum to give thelactone acid 19 (985 mg, 98%) as a white crystalline solid.

¹H NMR (500 MHz, CDCl₃) δ 4.59 (dd, J=5.3, 5.3 Hz, 1H, H6), 4.57 (d,J=10.5 Hz, 1H, C3H_(a)H_(b)), 4.52 (d, J=10.5 Hz, 1H, C3H_(a)H_(b)),2.96 (d, J=15.7 Hz, 1H, C8H_(a)H_(b)), 2.54 (d, J=15.7 Hz, 1H,C8H_(a)H_(b)), 2.46 (ddd, J=12.6, 5.0, 2.3 Hz, 1H, C7H_(endo)H_(exo)),2.03 (ddddd, J=12.3, 12.3, 5.3, 2.8, 2.8 Hz, 1H, H5exo), 1.93 (ddd,J=12.3, 8.7, 3.1 Hz, 1H, H4endo), 1.78 (ddd, J=12.3, 12.3, 5.6 Hz, 1H,H4exo), 1.75 (d, J=12.5 Hz, 1H, C7H_(endo)H_(exo)), and 1.63 (ddd,J=12.7, 8.8, 5.6 Hz, 1H, H5endo). ¹H NMR (500 MHz, acetone-d₆) δ 4.58(d, J=10.4 Hz, 1H, C3H_(a)H_(b)), 4.51 (dd, J=5.3, 5.3 Hz, 1H, H6), 4.42(d, J=10.4 Hz, 1H, C3H_(a)H_(b)), 2.86 (d, J=15.6 Hz, 1H, C8H_(a)H_(b)),2.62 (d, J=15.6 Hz, 1H, C8H_(a)H_(b)), 2.22 (ddd, J=12.4, 5.0, 2.3 Hz,1H, C7H_(endo)H_(exo)), 2.09-1.99 (m, 1H), 1.94-1.86 (nfom, 1H), 1.84(d, J=12.4 Hz, 1H, C7H_(endo)H_(exo)), and 1.78-1.66 (m, 2H).

¹³C NMR (125 MHz, acetone-d₆) δ 179.5, 171.7, 92.8, 77.0, 69.6, 53.8,45.5, 39.4, 29.4, and 25.1.

IR (neat): 3300-2600 (br), 2989, 1706, 1397, 1177, 1459, 1147, 1348,997, 961, 826, and 604 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₂NaO₅ ⁺ [M+Na⁺] requires 235.0577; found235.0579.

mp: 173-176° C.

Preparation of(±)-4,7-dihydro-3a,7a-(methanoxymethano)benzofuran-2,10(3H)-dione (20)

Hydrogenated lactone acid 19 (200 mg, 0.94 mmol) was suspended inchloroform (10 mL) in a 50 mL, two-neck, round-bottom flask.Trifluoromethanesulfonic acid (TfOH, 16 μL, 20 mol %) was added. Abrown-black color was immediately observed. This solution was stirredfor 12 h at 80° C., at which time the color had become somewhat darker.The chloroform was concentrated in vacuo and the residue was purified byflash column chromatography on SiO₂ (hexanes/EtOAc, 3:1) to give thedilactone 20 (56 mg, 30%), that coeluted with a portion of isomer 21, asa colorless oil.

¹H NMR (500 MHz, CDCl₃) δ 5.96-5.91 (m, 1H, H5 or H6), 5.91-5.86 (m, 1H,H5 or H6), 4.59 (d, J=10.9 Hz, 1H, C8H_(a)H_(b)), 4.20 (d, J=10.9 Hz,1H, C8H_(a)H_(b)), 3.10 (d, J=18.3 Hz, 1H, C3H_(a)H_(b)), 2.74 (d,J=18.3 Hz, 1H, C3H_(a)H_(b)), 2.68-2.56 (m, 2H), and 2.55-2.45 (m, 2H).

¹³C NMR (125 MHz, CDCl₃) δ 178.8, 172.4, 125.6, 124.8, 88.0, 75.0, 48.1,38.2, 31.0, and 29.9.

IR (neat): 3047, 2963, 2940, 2854, 1768, 1463, 1417, 1308, 1239, 1191,1018, and 940 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₀NaO₄ ⁺ [M+Na⁺] requires 217.0471; found217.0481.

TLC: R_(f)0.52 (5:1 Hex/EtOAc).

Preparation of(±)-6,7-dihydro-3a,7a-(methanoxymethano)benzofuran-2,10(3H)-dione (21)

Hydrogenated lactone acid 19 (200 mg, 0.94 mmol) was suspended inchloroform (10 mL) in a 50 mL, two-neck, round-bottom flask.Trifluoromethanesulfonic acid (TfOH, 16 μL, 20 mol %) was added. Abrown-black color was immediately observed. This solution was stirredfor 2 h at 80° C., at which time the color had darkened. The chloroformwas concentrated in vacuo and the residue was purified by flash columnchromatography on SiO₂ (3:1 hexanes:EtOAc elution) to give the dilactone21 (54 mg, 30%), that coeluted with a portion of isomer 20, as acolorless oil.

¹H NMR (500 MHz, CDCl₃) δ 6.06 (ddd, J=9.6, 5.6, 2.1 Hz, 1H, H5), 5.80(ddd, J=9.8, 2.5, 1.1 Hz, 1H, H4), 4.52 (d, J=11.1 Hz, 1H,C8H_(a)H_(b)), 4.31 (d, J=11.1 Hz, 1H, C8H_(a)H_(b)), 3.20 (d, J=18.2Hz, 1H, C3H_(a)H_(b)), 2.68 (d, J=18.2 Hz, 1H, C3H_(a)H_(b)), 2.40(ddddd, J=18.7, 5.9, 5.9, 1.9, 1.9 Hz, 1H, C6H_(a)H_(b)), 2.27 (ddd,J=13.8, 5.8, 2.2 Hz, 1H, C7H_(a)H_(b)), 2.19-2.09 (m, 1H, C6H_(a)H_(b)),and 1.78 (ddd, J=13.6, 12.0, 6.2 Hz, 1H, C7H_(a)H_(b)).

¹³C NMR (125 MHz, CDCl₃) δ 176.0, 172.3, 130.3 (C5), 122.5 (C4), 87.6(C7a), 71.5 (C8), 50.0 (C3a), 38.4 (C3), 26.3 (C7), and 22.8 (C6)(assignments supported by analysis of the HMQC and HMBC spectra).

IR (neat): 3075, 3100, 2925, 2875, 1763, 1469, 1421, 1288, 1230, 1188,1154, 1015, 936, 709, and 617 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₀NaO₄ ⁺ [M+Na⁺] requires 217.0471; found217.0479.

TLC: R_(f)0.52 (5:1 Hex/EtOAc).

Preparation of(±)-tetrahydro-3a,7a-(methanoxymethano)benzofuran-2,10(3H)-dione (22)

Alkene 21 (800 mg, 4.1 mmol) was dissolved in acetone (40 mL) in a 100mL, two-neck, round-bottom flask. To this mixture was added palladium onactivated carbon (10% Pd/C, 80 mg). The vessel was closed with a rubberseptum and H₂ gas was introduced via a balloon. The mixture was stirredat room temperature for 4 h. The resulting suspension was filteredthrough a plug of Celite®. The filtrate was concentrated under reducedpressure and the crude material was purified by flash columnchromatography (EtOAc/MeOH, 2:1) to give 22 (767 mg, 95%) as a whitesolid.

¹H NMR (500 MHz, CDCl₃) 4.49 (d, J=11.2 Hz, 1H, C8H_(a)H_(b)), 4.33 (d,J=11.2 Hz, 1H, C8H_(a)H_(b)), 2.96 (d, J=18.0 Hz, 1H, C3H_(a)H_(b)),2.74 (d, J=18.0 Hz, 1H, C3H_(a)H_(b)), 2.22 (dddd, J=14.6, 3.6, 3.6, 1.5Hz, 1H), 2.13 (dddd, J=14.6, 3.4, 3.4, 2.0 Hz, 1H), 1.94-1.88 (m, 1H),1.82-1.76 (m, 1H), 1.59 (ddd, J=14.5, 13.1, 4.6 Hz, 1H), 1.54 (ddd,J=14.6, 12.9, 4.2 Hz, 1H), 1.36 (ddddd, J=12.6, 12.6, 12.6, 3.2, 3.2 Hz,1H), and 1.28 (ddddd, J=14.6, 12.8, 12.8, 3.4, 3.4 Hz, 1H).

¹H NMR (500 MHz, C₆D₆) δ 3.75 (d, J=11.1 Hz, 1H, C8H_(a)H_(b)), 3.35 (d,J=11.1 Hz, 1H, C8H_(a)H_(b)), 2.65 (d, J=17.9 Hz, 1H, C3H_(a)H_(b)),2.01 (d, J=17.9 Hz, 1H, C3H_(a)H_(b)), 1.34 (dddd, J=14.4, 3.4, 3.4, 2.0Hz, 1H), 1.24 (dddd, J=14.4, 2.1, 2.1, 1.2 Hz, 1H), 0.96-0.89 (m, 1H),0.82 (dddddd, J=13.6, 3.1, 3.1, 3.1, 3.1, 1.2 Hz, 1H), 0.75 (ddd,J=14.6, 13.3, 4.7 Hz, 1H), 0.73 (ddd, J=14.9, 12.8, 4.2 Hz, 1H), 0.40(ddddd, J=12.6, 12.6, 12.6, 3.4, 3.4 Hz, 1H), and 0.26 (ddddd, J=13.3,13.3, 13.3, 3.3, 3.3 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃) δ 178.4, 172.4, 87.6, 71.0, 48.1, 34.6, 30.2,28.0, 22.0, and 19.7.

IR (neat): 2941, 2867, 1776, 1461, 1379, 1237, 1189, 1042, 1003, and 921cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₀H₁₂NaO₄ ⁺ [M+Na+^(]) requires 219.0628;found 219.0626.

mp: 95-99° C.

Preparation of o-tolylacetic acid (23)

Hydrogenated lactone acid (19, 2.0 g, 9.4 mmol) was placed in a 50 mL,two-neck, round-bottom flask. Trifluoromethanesulfonic acid (TfOH, 80μL, 1.0 mmol) was added; and the mixture was purged with N₂, tightlycapped, and heated to 160° C. for 7 h. The reaction time depended onscale for this heterogeneous process. Reaction progress could bemonitored by ¹H NMR analysis of an aliquot. The reaction mixture turneddeep brown. The reaction mixture was dissolved in EtOAc (ca. 10 mL) andthat solution was washed with water (ca. 10 mL). The organic layer waswashed with brine, dried with MgSO₄, filtered, and concentrated in vacuoto give crude o-tolylacetic acid 23 (1.3 g, 7.7 mmol, 81%) as a darkbrown solid. A portion (350 mg) was purified by MPLC (3:1 hexanes:EtOAcelution) to give a pale yellow solid (332 mg; 77% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.22-7.16 (m, 4H), 3.67 (s, 2H, CH₂CO₂H), and2.33 (s, 3H, CH₃).

mp: 84-86° C. (lit. 88-89° C.; Chauffe, L., et al., J. Org. Chem. 1966,31, 3758-3764).

Preparation of 2-(o-tolyl)ethanol (S1)

A solution of o-tolylacetic acid 23 (330 mg, 2.20 mmol) in dry ether (5mL) was slowly added to a stirred mixture of LiAlH₄ (180 mg, 4.7 mmol)in dry ether (5 mL) in a 100 mL round-bottom flask. Once gas evolutionhad subsided, the mixture was refluxed for 3 h. The mixture was quenchedby careful addition of 0.2 mL of water, 0.2 mL of 15% NaOH aqueoussolution, and 1.2 mL of water. The insoluble salts were removed byfiltration, and the organic layer was washed with brine and dried overanhydrous MgSO₄. The ether was removed on a rotary evaporator with anambient temperature bath to leave 2-(o-tolyl) ethanol (S1) (Sakai, N.,et al., Eur. J. Org. Chem. 2011, 3178-3183) as a light yellow liquid(219 mg, 1.61 mmol, 75%).

¹H NMR (500 MHz, CDCl₃) δ 7.22-7.10 (m, 4H), 3.85 (t, J=6.9 Hz, 2H,CH₂OH), 2.90 (t, J=6.8 Hz, 2H, CH₂Ar), 2.34 (s, 3H, CH₃), and 1.42 (brs, 1H, OH).

Preparation of 2-methylstyrene (24) and o-xylene (25)

2-(o-Tolyl) ethanol (S1, 34 mg, 0.25 mmol) and KOH pellets (85 mg, 1.5mmol) were added to a culture tube. The reaction mixture was heated in a160° C. oil bath for 1 h. The residue from the cooled mixture waspurified using MPLC (19:1, Hexanes:EtOAc elution) to give a mixture of2-methylstyrene (24) and o-xylene (25) as a coeluting, colorless liquid(17 mg, 0.15 mmol, 58%). The ratio, judged from analysis of the ¹H NMRspectrum, was 3.3:1 of 24:25.

¹H NMR (of the mixture of hydrocarbons, 500 MHz, CDCl₃) δ 7.49-7.46(nfom, 1H), 7.19-7.08 (m, 5H), 6.95 (dd, J=17.4, 11.0 Hz, 1H), 5.63 (dd,J=17.4, 1.3 Hz, 1H), 5.29 (dd, J=11.0, 1.3 Hz, 1H), 2.35 (s, 3H,styrenylCH₃), and 2.26 (s, 1.8H, xylenylCH₃s). (literature spectraldata: E. Alacid, C. Najera, J. Org. Chem. 2009, 74, 8191-8195).

C. Ring-Opening Metathesis Polymerization (ROMP) of Lactone Methyl Ester14^(Me) to Give 26

The lactone methyl ester 14^(Me) (100 mg, 0.45 mmol) was added to a 10mL culture tube and dissolved in CH₂Cl₂ (1 mL). Diethyl diallylmalonate(2-10 μL, 2-10 mg, 9-42 mmol, see Table 1) was added. The vial wassealed with a rubber septum and the solution and headspace were spargedwith argon gas. In a separate scintillation vial, a solution of GrubbsIII pre-catalyst [(SIMes)Ru(Cl₂)(3-Br-py)₂=CHPh ordichloro[1,3,bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-(benzylidene)bis(3-bromopyridine)ruthenium(II)]in CH₂Cl₂ was prepared and then added to the lactone methyl estersolution within 2 minutes of its preparation. This solution was allowedto stir at ambient temperature for 24 hours. Excess ethyl vinyl ether(0.5 mL) was added to arrest further metathesis events. The product waspurified by precipitation: the CH₂Cl₂ solution was added into methanol(200 mL) and stirred for ca. 30 min. The slurry was filtered and theoff-white solid was dried under vacuum overnight to provide 50-60 mg ofmaterial. All manipulations were carried out at ambient temperature.

26 (Sample from Entry 1)

¹H NMR (500 MHz, DMSO-d₆) δ 5.76 (br d, J=10.9 Hz, 2H), 5.6-5.3 (m, ═CH₂from terminating methylenes), 4.48 (br s, 1H), 4.29 (m, 2H), 3.60 (br s,3H), 2.96 (br d, J=17.4 Hz, 1H), 2.63 (br d, J=17.3 Hz, 1H), 2.32 (br s,1H), and 1.76 (br s, 1H).

TABLE 1 ^(a)Characterization data for two samples of ROMP polymer 26.Initiator M_(n) M_(n) T_(g) Entry (mol %) (theo) (NMR)^(b) M_(n)(SEC)^(c) M_(w) (SEC)^(c)

(° C.) 1 9.3 2.4 1.6 2.6 3.2 1.22 123 2 5.3 4.2 2.7 3.0 3.7 1.26 131^(a)M_(n) and M_(w) values in kg · mol⁻¹. ^(b)M_(n) from ¹H NMRanalysis, assuming every polymer has a vinyl group (i.e., RCH═CH₂) oneach of its termini - a reasonable assumption since even if a malonateunit is present (see MALDI below), that group should still be terminatedby a vinyl group. ^(c)vs. polystyrene standard (in CHCl₃).

D. General Procedure for the DA Reaction Between Furan 3, 5, 7, or 9 andIA (1)

An excess amount of the furan (ca. 20 equiv) was added to a capped flaskcontaining 1 (1 equiv) to form a slurry. The mixture was allowed to stirat room temperature. Aliquots of the mixture were periodically removedin order to monitor the progress of the DA reaction by ¹H NMR analysis,that was carried out immediately after each NMR sample was prepared. Toobtain useful signal to noise levels of the ¹H NMR resonances for theminor amounts of product often being observed, relatively concentratedsolutions of CDCl₃ NMR samples were used. The percent conversion to DAadducts was recorded as the equilibrium conversion in Table 10. When therelative amounts of observed species remained constant in twoconsecutive aliquots, it was deemed that equilibrium had been reached.The reaction time required to reach half of the equilibrium conversionis provided as t_(1/2) in Table 10. FIGS. 4-7 display the finalequilibrium ¹H NMR spectrum for each of the reactions shown in entries1-4 of Table 10.

E. Computational (DFT) Methodology Used and Free Energies and Geometriesfor 13′/13, 14′/14, 13′^(Me)/13^(Me), and 14′^(Me)/14^(Me)

Each of structures in Scheme 2B was subjected to a molecular mechanicsmulticonformational search in Macromodel (version 10.7). The resultingminima were each subjected to an M06-2X/6-31+G(d,p) optimizationcalculation with a “tight” cutoff and an “ultrafine” integration grid inGaussian 09 (Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120,215-241; M. J. Frisch, et al., Gaussian 09, Revision A.02, Gaussian,Inc., Wallingford Conn., 2009). This was followed by a frequencycalculation (at 298 K) to obtain the Gibbs energy for each conformer.Solvation in chloroform was accounted for by using the SMD solvationmodel. (V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009,113, 6378-6396). Each conformer was Boltzmann-weighted based on itsGibbs energy to obtain its mole fraction. The mole fractions of allconformers for each isomer were used to determine the overall(Boltzmann-averaged) Gibbs energy of that isomer.

F. NMR-Based Assignment of Relative Configuration to 4-Exo Vs. 4-Endo,Including Comparisons Between Computed and Experimental Chemical Shifts

To assign the structure of the endo vs. exo stereoisomers in theseseries of compounds, the following sequence of experiments were carriedout. First, the equilibrium mixture of products 4 was dissolved inacetone and quickly exposed to 10% Pd/C and hydrogen gas (1 atm) inorder to saturate the alkene, thereby arresting further cycloreversionto itaconic anhydride (1) and furan (3), a process that is promoted bythe simple act of dilution. The diastereomeric saturated analogs 4-h2were chromatographically separated and individually characterized.

Second, in order to correlate that isomer of 4-h2 came from that isomerof the alkene adducts 4 it was necessary to separate the latter pair. Amixture of the exo- and endo-isomers of 4 was quickly chromatographed onSiO₂ (MPLC), and ¹H NMR data were collected for each (in both CDCl₃ andC₆D₆). A sample of the slower eluting isomer of 4, immediately followingchromatographic separation, was then quickly reduced by H₂ to give thesame isomer of 4-h2, that eluted more slowly, thereby allowing thecorrelation of the two slower eluting isomers of each pair.

To aid in the assignment of relative configuration of each of thediastereomeric pairs, the NMR chemical shifts of each of the fourstructures of 4 and 4-h2 were computed in Gaussian 09 using DFT[B3LYP/6-311+G(2d,p)//M06-2X/6-31+G(d,p), both using SMD:CHCl₃].Optimizations were run using an “ultrafine” integration grid and weresubjected to a “tight” cutoff. A multiconformational search (carried outin Macromodel, version 10.7) resulted in only a single minimum energyconformation for each of these rigid anhydrides, making Boltzmannaveraging unnecessary. Experimental and computed values were thencompared (Tables 2-9). In order to reduce error, least-squares linearregression analysis of the experimental vs. the computed chemical shifts(δ_(exp) and δ_(comp), respectively) was carried out for each isomer.The corrected chemical shift values (δ_(corr)) were extracted from theresulting linear equation (δ_(corr)=slope×δ_(comp)+intercept). Thecorresponding corrected mean absolute error (CMAE) for the sets of boththe carbon and, especially, the proton chemical shifts (FIGS. 10 and 11)suggested that the structure of the faster eluting isomer in each pairwas 4-endo-h2 and 4-endo, while that of the less chromatographicallymobile isomer was 4-exo-h2 and 4-exo.

It is worth noting that NOE experiments did not provide a definitivebasis for confidently assigning either of these pairs of exo- andendo-diastereomers. Finally, these structural assignments were confirmedby the X-ray diffraction analysis of the diacid 5 derived from thefaster eluting, hydrogenated compound—4-endo-h2 (FIG. 12B). When thisanhydride was added to hot D₂O (or incubated in a homogenous solution ofaqueous acetone), it smoothly opened to the diacid 5.

Diagnostic features in the ¹H NMR spectral data of each diastereomer of4 were then useful to assess and deduce the relative configuration ofthe DA adducts prepared from additional furan derivatives (7, 9, and 11in Table 10). As shown in FIG. 9, these include (i) the multiplicity ofthe bridgehead proton adjacent to vs. remote from the spirocyclicquaternary carbon [H1 in, e.g., 4-exo was a simple doublet (J=ca. 2 Hz)whereas H4 was a dd (J=ca. 5 and 2 Hz) showing coupling to H3_(x) butnot H3_(n), because the H4/H3_(n) dihedral angle is near 90° ] and (ii)the differences in chemical shifts of the diastereotopic methyleneprotons at C3 and C4′ as well as the δ_(rel) values for the bridgeheadprotons, when present. Because the equilibrium concentration for all ofthese adducts was typically low (5-20%, Table 10), their spectral datawere recorded and analyzed from a mixture of the endo and exo adductsalong with the excess diene (i.e., furan derivative) and remaining IA(1) (FIG. 12 and FIGS. 4-7).

TABLE 2 Error correction for computed 4-endo-h2 ¹H chemical shifts.Scaled (Linearly Experimental Corrected) Scaled Atom Computed ShiftShift Error Shift Error 2 4.35 4.43 0.08 4.41 0.02 3-Endo 1.99 2.14 0.152.04 0.10 3-Exo 1.58 1.65 0.07 1.63 0.02 4-Endo 1.66 1.73 0.07 1.71 0.024-Exo 1.76 1.82 0.06 1.81 0.01 5 4.64 4.76 0.12 4.70 0.06 6-Endo 2.302.26 −0.04 2.35 −0.09 6-Exo 1.83 1.92 0.09 1.88 0.04 9 (pro-R) 3.21 3.220.01 3.27 −0.05 9 (pro-S) 2.81 2.76 −0.05 2.87 −0.11

TABLE 3 Error correction for computed 4-endo-h2 ¹³C chemical shifts.Experimental Scaled (Linearly Scaled Atom Computed Shift Shift ErrorCorrected) Shift Error 1 62.5 54.6 −7.9 61.3 −6.7 2 91.8 84.9 −6.9 89.4−4.5 3 29.0 24.6 −4.4 30.2 −5.6 4 32.9 29.2 −3.7 34.1 −4.9 5 84.7 78.2−6.5 84.2 −6.0 6 48.5 44.5 −4.0 45.3 −0.8 7 187.0 173.6 −13.4 188.1−14.5 8 182.5 168.7 −13.8 183.4 −14.7 9 49.2 44.2 −5.0 41.4 2.8

TABLE 4 Error correction for computed 4-exo-h2 ¹H chemical shifts.Scaled (Linearly Experimental Corrected) Scaled Atom Computed ShiftShift Error Shift Error 2 4.52 4.73 0.2055 4.57 0.16 3-Endo 1.97 1.80−0.17 2.02 −0.22 3-Exo 1.74 1.57 −0.17 1.79 −0.22 4-Endo 1.42 1.860.4357 1.48 0.38 4-Exo 1.78 1.88 0.1027 1.83 0.05 5 4.65 4.79 0.13694.70 0.09 6-Endo 1.42 1.63 0.2057 1.48 0.15 6-Exo 2.56 2.50 −0.0563 2.61−0.11 9 (pro-S) 3.19 3.09 −0.1 3.24 −0.15 9 (pro-R) 3.09 3.02 −0.06723.14 −0.12

TABLE 5 Error correction for computed 4-exo-h2 ¹³C chemical shifts.Experimental Scaled (Linearly Scaled Atom Computed Shift Shift ErrorCorrected) Shift Error 1 61.0 52.7 −8.3 54.6 −1.9 2 89.1 81.2 −7.9 84.8−3.6 3 30.0 26.5 −3.5 24.6 1.9 4 33.9 29.4 −4.5 29.2 0.2 5 83.9 77.4−6.5 78.1 −0.7 6 45.1 44.1 −1.0 44.5 −0.4 7 187.4 174.7 −12.7 173.4 1.38 182.7 169.0 −13.7 168.5 0.5 9 41.2 37.5 −3.7 44.2 −0.1

TABLE 6 Error correction for computed 4-endo ¹H chemical shifts.Computed Experimental Scaled (Linearly Scaled Atom Shift Shift ErrorCorrected) Shift Error 2 4.80 4.83 0.03 4.70 0.13 3 6.60 6.36 −0.24 6.40−0.04 4 7.01 6.66 −0.35 6.79 −0.13 5 5.14 5.2 0.06 5.02 0.18 6-endo 2.072.07 0.00 2.13 −0.06 6-exo 1.99 2.05 0.06 2.05 0.00 9 (pro-S) 3.18 3.08−0.10 3.17 −0.09 9 (pro-R) 3.20 3.2 0.00 3.20 0.00

TABLE 7 Error correction for computed 4-exo-h2 ¹³C chemical shifts.Experimental Scaled (Linearly Scaled Atom Computed Shift Shift ErrorCorrected) Shift Error 1 57.4 49.8 −7.6 52.2 −2.4 2 93.4 86.4 −7.0 86.00.4 3 141.4 130.5 −10.9 131.0 −0.5 4 149.1 138.5 −10.6 138.2 0.3 5 86.580.0 −6.5 79.5 0.5 6 44.7 41.7 −3.0 40.3 1.4 7 186.3 173.5 −12.8 173.10.4 8 182.9 169.5 −13.4 169.9 −0.4 9 47.1 42.7 −4.4 42.5 0.2

TABLE 8 Error correction for computed 4-exo ¹H chemical shifts. ComputedExperimental Scaled (Linearly Scaled Atom Shift Shift Error Corrected)Shift Error 2 5.01 5.11 0.10 4.88 0.23 3 6.84 6.48 −0.36 6.59 −0.11 47.08 6.71 −0.37 6.82 −0.11 5 5.18 5.26 0.08 5.04 0.22 6-endo 1.39 1.530.14 1.50 0.03 6-exo 2.78 2.71 −0.07 2.79 −0.08 9 (pro-S) 3.00 2.77−0.23 3.00 −0.23 9 (pro-R) 2.68 2.76 0.08 2.70 0.06

TABLE 9 Error correction for computed 4-exo-h2 ¹³C chemical shifts.Experimental Scaled (Linearly Scaled Atom Computed Shift Shift ErrorCorrected) Shift Error 1 58.0587 49.70 −8.4 52.8 −3.1 2 90.7399 83.00−7.7 82.8 0.2 3 143.1034 133.20 −9.9 130.8 2.4 4 151.533 140.60 −10.9138.5 2.1 5 86.2166 79.60 −6.6 78.6 1.0 6 43.6927 38.50 −5.2 39.7 −1.2 7187.6446 175.10 −12.5 171.6 3.5 8 182.777 160.00 −22.8 167.1 −7.1 943.2746 41.40 −1.9 39.3 2.1

G. Discussion

The reaction of IA (1) with various furans was investigated. A hallmarkof furans as participants in DA cycloaddition chemistry is the fact thatthe enthalpic change upon formation of the DA adduct is not nearly asfavorable as is the case for more typical dienes. This is because lossof the furan aromatic resonance stabilization accompanies this class ofcycloaddition. An important consequence of these thermodynamic facts isthat DA adducts derived from furans have only rarely been accessed withsufficient efficiency to be useful in sustainable materials applications(Mahmoud, E., et al., Green Chem. 2014, 16, 167-175; Shiramizu, M.,Toste, F. D., Chem. Eur. J. 2011, 17, 12452-12457; Williams, C. L., etal., ACS Catal. 2012, 2, 935-939; Pacheco, J. J., Davis, M. E.,Proceedings of the National Academy of Sciences 2014, 111, 8363-8367).As demonstrated herein anhydride opening along with crystal latticeforces, as enthalpic driving forces, can overcome otherwise sub-optimalthermodynamic parameters of furan DA reactions. Specifically, furfurylalcohol (FA, 2) and IA (1) form a crystalline adduct, the lactone acid14 (Scheme 2A), that drives the overall process to high conversion.

The reactions between IA (1) and a variety of simple furans, startingwith furan (3) itself were first investigated. In one experiment IA wasdissolved in 20 equivalents of furan and held at ambient temperature.Aliquots were periodically withdrawn and dissolved in CDCl₃ to monitorthe progress of reaction. It was important in this kind of analysis thatthe spectral data be recorded soon after sample preparation, because theretro-Diels-Alder reaction was also operative at room temperature, anddilution (here, from neat to NMR sample concentration) shifts theequilibrium composition of any bimolecular to unimolecular processtoward the starting pair of reactants (here, 1+3). Two diastereomericproducts, 4-endo and 4-exo, are produced (FIG. 12A and Table 10, entry1). Even at early time points, the formation of these two products wereobserved at nearly identical rates. After 40 hours the system hadessentially reached its equilibrium state that is comprised of a ratioof 73% of the initial IA (1) and 27% of the sum of the two DA adducts.At equilibrium, there was a very slight predominance of 4-endo over theamount of 4-exo. These diastereomeric DA adducts were sufficientlystable to be isolable by rapid chromatographic separation on silica gel,even though some retro-DA reaction was occurring as the solutions werebeing manipulated. Isolated solid-state samples of each isomer wereconsiderably more stable. Upon dissolution in CDCl₃ or C₆D₆, each isomerbegan to slowly revert to 1 and 3 (ca. 50% conversion after 6 h),consistent with the rate of their formation and final equilibriumratios.

TABLE 10 Reactions of itaconic anhydride (1) with the series of furanderivatives 3, 6, 8, and 10 (20 equiv) at ambient temperature equil.conv. 20:1 (isomer ratio) entry molar ratio endo exo [t_(1/2) to equil]1    

27% (1:1) [8 h] 2

ca. 5% (2:1) [0.25 h] 3    

ca. 13% (11:8:3:1)^(a) [10 h] 4

ca. 20% (8:6:2:1)^(b) [24 h]

The assignment of the diastereomeric relationship within each of 4-exoand 4-endo was initially based on detailed analyses of NMR data asdescribed herein above. This was subsequently confirmed by an X-raystructure of the diacid 5 (FIG. 12B) obtained by catalytic hydrogenationof 4-endo to the derivative 4-endo-h2, that was then hydrolyzed to thecrystalline diacid that. Diagnostic features in the 1H NMR spectral dataof each diastereomer of 4 were then useful in assessing the relativeconfiguration of the DA adducts prepared from additional furanderivatives (4, 7, 9, and 11 in Table 10).

2,5-Dimethylfuran (6) was the next diene studied, again in an experimentwhere it was used as the reaction solvent and in ca. 20-fold excess overIA (1). The results are summarized in Table 10 (entry 2). The reactionof 6 with 1 was notably faster than that of furan (t_(1/2)˜15 min vs. ˜8h at 23° C.), consistent with the greater electron density in diene 6.However, the reaction proceeded to a considerably lower equilibriumconversion (approximately 5%) of the sum of DA adducts 7-endo and 7-exo,that reflects the greater steric compression between the substituents onthe spirocyclic carbon and the adjacent (proximal) bridgehead methylgroup present in adducts 7 vis-à-vis adducts 4. At an intermediate timepoint (10 min, approximately 3% conversion), the formation of the majorisomer had outpaced that of the minor to the extent of ca. 2:1, a ratiothat remained essentially constant.

2-Acetoxymethylfuran (10) was another diene substrate that was studied(Table 10, entry 4). At equilibrium, the IA DA adducts 11 were formed,again to an extent intermediate between that of 4 vs. 7. This wasobserved to be the slowest of all reactions we studied, consistent withthe acetoxymethyl substituent having weakly electron withdrawingcharacter. As was the case for 9, at equilibrium the distal isomerspredominated. The assignments of structure to the distal vs. proximalsubstitution patterns among the isomers of 9 and 11 were based on thedifference in coupling patterns of the resonances for the bridgeheadprotons (at C4) in each (see SI). HMQC and HMBC NMR analyses also wereconsistent with these assignments.

The reaction between the bio-derived FA (2) and IA (1) was theninvestigated. Initially, the behavior of an equimolar mixture of thisdiene/dienophile pair in CDCl₃ solution (˜1.5 M) was monitored. Afterbeing held at 55° C. for 10 minutes, a few percent of total conversionto a mixture of four DA adducts was detected that is consistent with thebehavior (rate and ratio) observed for the reaction between the acetate10 and 1. By analogy, it was presumed that these four compounds were amixture of the isomeric anhydrides 12 (Scheme 2A). When this reactionsolution was examined after 7 days, a new, fifth, component was seen toemerge to the extent of ca. 15% relative to the unconsumed IA (1). Theappearance of (i) a broad downfield resonance and (ii) a pair ofdownfield doublets (δ 4.62 and 4.83, J_(ab)=10.8 Hz) in this new,dominant compound suggested that a carboxylic acid lactone had formed;it is reasonable to anticipate a conversion of one of 12-prox-exo or12-prox-endo to a ring-opened lactone acid by one of the four pathwaysimplied by arrows “a” or “b” in 12-prox-exo or “a′” or “b′” in12-prox-endo (Scheme 2A). The favorable free energy change associatedwith anhydride opening provides an additional driving force to helpfavor the DA adduct(s).

An additional important discovery occurred when an equimolar mixture of1 and 2 was allowed to react in the bulk. A suspension of solid 1 (95%grade) in liquid 2 (98% grade) at ambient temperature changed over timein consistency. After 3-4 hours the initial heterogeneous slurry couldno longer be magnetically stirred; we could identify in the NMR spectrumof an aliquot the presence of all four isomeric anhydrides 12 (Scheme2A) to the total extent of ca. 5%, along with a significant amount ofthe same fifth component mentioned in the paragraph above. After 10 hthe composition of the bulk reaction mixture was that of a paste, andafter 18 h it had turned to a solid mass. This material was comprised oflargely a single component, having the same spectral properties as thoseof the new, fifth component that had appeared after 7 days in thehomogenous CDCl₃ solution experiment described above. The ¹³C NMRspectrum of this compound showed a carbonyl resonance at δ 177.8 ppm,suggestive that it contained a 5-membered butyrolactone ring (J. B.Lambert, et al., J. Org. Chem. 1983, 48, 3982-3985) X-ray diffractionshowed the structure to be that of the lactone acid 14, arisingtherefore from (event “a” in) 12-prox-exo.

Analysis of aliquots from the bulk reaction mixture over time showed thesteady-state mixture of the four DA adducts 12 transforming to largelythe single component 14, establishing the ready reversibility of each of12 back to IA (1) and FA (2). The ¹H NMR spectrum of an aliquot takenfrom an equimolar mixture after 2 days is shown in FIG. 13. From carefulintegration the chemical yield for formation of 14 was determined to be94%. The driving force for the conversion of IA+FA to 14 comes both from(i) the opening of the anhydride as well as (ii) the crystallization ofthe product from a dynamic, interconverting mixture of multiplecomponents.

A sample removed from the bulk mixture of 1 and 2 after just 30 minuteswas immediately chromatographed on silica gel. Small amounts(approximately 1 mg each) of three samples were unearthed, each in <1%yield but each highly informative in various ways. The dilute CDCl₃solution of each of the anhydrides 12-dist-endo and 12-dist-exo,assigned as such by comparative NMR analyses with some of the previousDA adducts, was observed to begin reverting to 1 and 2 at roomtemperature in a matter of minutes. The third sample proved to be anacid lactone isomeric with 14. It contained ˜20% of a second compoundwhose ¹H NMR resonances suggested it to be the anhydride 12-prox-endo.Within a day in CDCl₃, this anhydride had converted to the same, newacid lactone. By a series of correlation experiments it was concludedthat the structure of this new lactone was that of 13, arising by theattack indicated by “b′” in structure 12-prox-endo (FIG. 13, spectruma).

Monitoring the thermal behavior of a CDCl₃ solution of the lactone acid14 was also informative. At 80° C. formation of a 1:4 mixture of the twomono-furfuryl itaconate esters 15a and 15b (see below for structureassignment) was observed. The formation of 15b cannot arise from directretro-DA reaction of 14. Instead 14 apparently reverts to 12-prox-exoand, in turn 2 and 1, that then can proceed to the mixture of 15a and15b. All of these intermediates were detectable through ¹H NMRmonitoring. To probe whether 14 can produce 15a directly by a retro-DAreaction, 14 was converted to the methyl ester 14^(Me). This compoundproved to be quite stable at 80° C. in CDCl₃ and only upon heating to140° C. in the melt did it finally revert solely to the ester 15a^(Me).An authentic sample of 15a^(Me) was produced by Mitsunobu esterificationreaction between FA (2) and the commercially available mono-methylitaconate 16. The rate of the retro-DA reaction of 14^(Me) suggests that14 does not proceed directly to 15a. Addition of alcohols IA (1) isknown to occur faster at the non-conjugated carbonyl carbon (Cheng, X.,et al., Org. Lett. 2014, 16, 1414-1417). When a 1:1 mixture of IA andbenzyl alcohol, a DA-silent mimic of FA (2), was heated at 80° C., asimilar mixture of analogous mono-benzyl itaconates was formed.

Isomeric lactone acid 13 was converted to the methyl ester 13^(Me). Likeits analog 14^(Me), this ester also showed clean retro-DA behavior whenheated neat at 140° C. (partial reversion after 1 min and complete after5 min). Only the mixed diester 15b^(Me) was produced, verifying that 13embodied a valero- rather than butyrolactone. All told, given the subtleand multi-faceted interplay of kinetic and thermodynamic factors withinthis array of competitive processes, it is notable that a singlemetastable adduct (i.e., 14) arises through trivial manipulation and inhigh yield. Unraveling the process to the extent captured in Scheme 2Arequired critical interrogation of minor components present in ¹H NMRspectra at numerous junctures.

With a robust process in hand for producing a 100% bio-derived compoundwith a novel structure, several transformations with an eye towardproduction of monomers having potential utility in polymer synthesiswere investigated. The reactivity of 14 and 14^(Me) was explored under anumber of reaction conditions that are either reagent free or useinexpensive reagents, and/or that are amenable to large-scale, and/orthat are free of byproduct formation. Such non-limiting reaction typesinclude catalytic hydrogenation, pyrolysis, and simple acid- orbase-catalyzed transformations. Scheme 3 summarizes some of thesereactions.

Treatment of either 14 or 14^(Me) at ambient temperature with a strongBrønsted acid (e.g., TfOH), either as a neat sample or in chloroformsolution, resulted in loss of water or methanol, respectively, andconcomitant formation of the bis-lactone diene 17. The structure of anisolated and purified sample (40% yield) of this interestingdioxapropellane derivative was supported by both 1D and 2D NMRspectroscopic studies. This diene was further converted under thereaction conditions to 3-isochromanone (18); the maximum extent ofaccumulation of 17 under the conditions we explored was ca. 50%.Isochromenone 18 is known to polymerize in a Friedel-Crafts sense when aneat sample is heated at 120° C. in the presence of TfOH (Suzuki, A. etal., J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 2214-2218).

Either 14 or 14^(Me) could be smoothly reduced by dihydrogen overpalladium on carbon to give 19 or 19^(Me), respectively. The former(acid) could also be converted to the latter (ester) by Fischeresterification. Upon treatment again with TfOH in chloroform solution,now at 80° C., either of 19 or 19^(Me) could be dehydrated to thedilactone mono-enes 20 and 21. These reactions were slower than those ofthe oxanorbornenes 14/14^(Me) to 17, presumably because the ring-openingof the ether bridge no longer results in formation of an allyliccarbenium ion. When either of 19 or 19^(Me) was heated in the bulk withTfOH at 160° C., 20 and 21 were again produced, but further reactionensued-namely, the production of 2-methylphenylacetic acid (23),accompanied by loss of CO₂. Arene 23 was isolated in 77% yield followingchromatographic purification. A sample of this acid 1 was reduced withlithium aluminum hydride to the corresponding phenethanol derivative andthen dehydrated at 160° C. over molten KOH to give a mixture of2-methylstyrene (24) and o-xylene (25). Alternatively, the esters can bereduced to alcohols by hydrogen gas using the Milstein/Saudan family ofcatalysts (Zhang, J., et al., Angew. Chem. Int. Ed. 2006, 45, 1113-1115;Saudan, L. A., et al., Angew. Chem. Int. Ed. 2007, 46, 7473-7476). Noneof the transformations described in Scheme 3, including the dehydrationof 2-(2-methylphenyl)ethanol, has been optimized.

In addition, a ring-opening metathesis polymerization (ROMP) of themonomer 14^(Me) (Scheme 4) was performed. The Grubbs-III initiatorinduced polymerization of a methylene chloride solution of the strainedalkene 14^(Me). An analogous ROMP was recently reported for 27, the DAadduct between cyclopentadiene and dimethyl itaconate (Winkler, M., etal., Macromolecules 2015, 48, 1398-1403). In contrast to the behaviourof norbornene derivative 27, that lacked bridgehead substituents, aninitiator diene (diethyl diallylmalonate) was added to promote the ROMPof 14^(Me). MALDI analysis suggested that the majority of polymermolecules were both initiated and terminated with ═CH₂ groups.Presumably the bulk of the quaternized bridgehead carbon in 14^(Me)provides a steric barrier that is best accommodated by methylidenemoieties (from ethylene) in the first and/or second steps ofpropagation.

Thus, lactone acid 14 was produced in high yield (94%) under efficientand mild reaction conditions (e.g., 1:1 mixture of IA (1) and FA (2),neat, ambient temperature). Moreover, 14 can be readily transformed intoa variety of derivatives (17-25, Scheme 3) that have potentialnon-limiting utility as monomers in sustainable polymer synthesis (e.g.,compound 26, Scheme 4).

Example 2. Preparation of(±)-2-(2-((3aR,6R)-1-Oxo-6,7-dihydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetoxy)ethylacrylate (100)

Hydroxyethyl acrylate (147 mg, 1.27 mmol) was dissolved in THF (10 mL).Acid 14 (280 mg, 1.33 mmol), EDCI (293 mg, 1.52 mmol), and DMAP (77 mg,0.64 mmol) were added, resulting in a suspension that was stirred atroom temperature for 3 h. Dilute aqueous HCl was added and the resultingmixture was extracted with 4 mL of methylene chloride. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1:1 hexanes:EtOAcelution) to give 100 (325 mg, 1.05 mmol, 83%) as a colorless liquid.

¹H NMR (500 MHz, CDCl₃) δ 6.58 (dd, J=5.8, 1.7 Hz, 1H), 6.50 (d, J=5.8Hz, 1H), 6.47 (dd, J=17.3, 1.3 Hz, 1H), 6.16 (dd, J=17.3, 10.5 Hz, 1H),5.90 (dd, J=10.5, 1.3 Hz, 1H), 5.06 (dd, J=4.7, 1.7 Hz, 1H), 4.82 (d,J=10.8 Hz, 1H), 4.63 (d, J=10.8 Hz, 1H), 4.43-4.33 (m, 4H), 2.56 (dd,J=12.3, 4.7 Hz, 1H), 2.56 (d, J=14.7 Hz, 1H), 2.37 (d, J=14.7 Hz, 1H),and 1.52 (d, J=12.3 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃) δ 177.0, 169.3, 166.0, 138.3, 131.7, 130.7,128.0, 94.1, 78.8, 68.7, 63.1, 62.0, 52.1, 39.9, and 36.7.

IR (neat): 2959, 1773, 1726, 1410, 1325, 1274, 1179, 1133, 998, 969,854, and 810 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₅H₁₆NaO₇ [M+Na⁺] requires 331.0788; found331.0780.

Example 3. Preparation of(±)-2-(2-((3aR,6S)-1-Oxotetrahydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetoxy)ethylacrylate (200)

Hydroxyethyl acrylate (154 mg, 1.33 mmol) was dissolved in THF (10 mL).Acid 19 (280 mg, 1.33 mmol), EDCI (303 mg, 1.58 mmol), and DMAP (83 mg,0.69 mmol) were added, resulting in a suspension that was stirred atroom temperature for 3 h. Dilute aqueous HCl was added and the resultingmixture was extracted with 4 mL of methylene chloride. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1:1 hexanes:EtOAcelution) to give 200 (320 mg, 1.03 mmol, 78%) as a colorless liquid.

¹H NMR (500 MHz, CDCl₃) δ 6.45 (dd, J=17.3, 1.4 Hz, 1H), 6.14 (dd,J=17.3, 10.5 Hz, 1H), 5.88 (dd, J=10.5, 1.4 Hz, 1H), 4.57 (t, J=5.3 Hz,1H), 4.53 (d, J=10.4 Hz, 1H), 4.50 (d, J=10.5 Hz, 1H), 4.43-4.33 (m,4H), 2.91 (d, J=15.3 Hz, 1H), 2.53 (d, J=15.3 Hz, 1H), 2.42 (ddd,J=12.6, 5.0, 2.3 Hz, 1H), 2.00 (dddd, J=14.9, 12.1, 5.7, 2.8 Hz, 1H),1.93 (ddd, J=12.1, 8.7, 3.2 Hz, 1H), 1.75 (ddd, J=12.2, 12.2, 5.6 Hz,1H), 1.75 (d, J=12.6 Hz, 1H), and 1.62 (ddd, J=12.4, 8.7, 5.6 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃) δ 178.6, 169.5, 165.9, 131.7, 127.9, 91.8,76.4, 69.1, 63.0, 62.0, 53.1, 44.9, 39.1, 29.0, and 24.6.

IR (neat): 2963, 1773, 1727, 1410, 1327, 1271, 1189, 1174, 1127, 1006,964, 850, and 811 cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₅H₁₈NaO₇ [M+Na⁺] requires 333.0945; found333.0947.

Example 4. Preparation of(±)-2-(2-((3aR,6S)-1-Oxotetrahydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetoxy)ethylmethacrylate (300)

Hydroxyethyl acrylate (173 mg, 1.33 mmol) was dissolved in THF (10 mL).Acid 19 (280 mg, 1.33 mmol), EDCI (290 mg, 1.51 mmol), and DMAP (86 mg,0.70 mmol) were added, resulting in a suspension that was stirred atroom temperature for 3 h. Dilute aqueous HCl was added and the resultingmixture was extracted with 4 mL of methylene chloride. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1:1 hexanes:EtOAcelution) to give 300 (315 mg, 1.03 mmol, 73%) as a colorless liquid.

¹H NMR (500 MHz, CDCl₃) δ 6.11 (dq, J=1.5, 1.0 Hz, 1H), 5.58 (dq, J=1.5,1.5 Hz, 1H), 4.54 (t. J=5.3 Hz, 1H), 4.50 (d, J=10.5 Hz, 1H), 4.46 (d,J=10.5 Hz, 1H), 4.36-4.29 (m, 4H), 2.88 (d, J=15.3 Hz, 1H), 2.49 (d,J=15.3 Hz, 1H), 2.39 (ddd, J=12.6, 5.0, 2.3 Hz, 1H), 1.97 (tdd, J=10.9,5.2, 2.2 Hz, 1H), 1.92 (dd, J=1.5, 1.0 Hz, 3H), 1.89 (ddd, J=12.1, 8.7,3.2 Hz, 1H), 1.72 (ddd, J=12.2, 12.2, 5.6 Hz, 1H), 1.75 (d, J=12.6 Hz,1H), and 1.59 (ddd, J=12.5, 8.7, 5.6 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃) δ 178.6, 169.5, 167.1, 135.9, 126.3, 91.8,76.4, 69.1, 63.1, 62.2, 53.1, 44.9, 39.2, 29.0, 24.6, and 18.3.

IR (neat): 2960, 1773, 1719, 1458, 1322, 1297, 1162, 1129, 1008, and 938cm⁻¹.

HRMS (ESI-TOF): Calcd for C₁₆H₂₀NaO₇ [M+Na⁺] requires 347.1101; found347.1111.

Example 5. AIBN Initiated Free Radical Polymerization of Compound 100

A solution of 100 (80 mg, 0.260 mmol) and2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 3.7 mg, 0.024mmol) was prepared. After the full dissolution of AIBN in the acrylate,the solution was transferred into a 5 mL round-bottom flask and degassedthrough a series of three freeze-pump-thaw cycles and then sealed undervacuum. The reaction mixture was heated at 70° C. for 24 h. The reactionmixture was allowed to cool to ambient temperature to give a clear diskthat was insoluble in all common solvents, suggestive of a cross-linkedstructure.

IR (neat, selected peaks): 2959, 1773, 1722, 1176, and 968 cm⁻¹.

DSC T_(g)=50° C. (See FIG. 19)

Example 6. AIBN Initiated Free Radical Polymerization of Compound 200

A solution of 200 (160 mg, 0.516 mmol) and2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 4.1 mg, 0.027mmol) was prepared. After the full dissolution of AIBN in the acrylate,the solution was transferred into a 5 mL round-bottom flask and degassedthrough a series of three freeze-pump-thaw cycles and sealed undervacuum. The reaction mixture was heated at 70° C. for 24 h. The reactionmixture was allowed to cool to ambient temperature and a portion of thecontents was analyzed by ¹H NMR spectroscopy.

¹H NMR (500 MHz, d₆-DMSO): δ 4.60-4.50 (m, 2.0H), 4.50-4.42 (m, 1.0H),4.30-4.10 (m, 4.0H), 2.35-2.20 (m, 1.1H), 2.15-2.06 (m, 1.5H), 1.90-1.75(m, 3.0H), and 1.72-1.58 (m, 3.5H).

IR (neat, selected peaks): 2998, 2939, 1778, 1461, 1383, 1183, and 1149cm⁻¹.

Example 7. RAFT Polymerization of Compound 200

AIBN (0.08 equiv, 0.16 mg, 1.0 μmol) was added to a 10 mL Schlenk flask.2-{[(Dodecylthio)carbonothioyl]thio}-2-methylpropanoic acid (DDMAT, 1.0equiv, 14.2 mg, 39.2 μmol) and acrylate 200 (18 equiv, 224 mg, 0.723mmol) were added. The headspace was degassed through severalfreeze-pump-thaw cycles, under static vacuum, until bubbling no longerwas observed during thawing. Nitrogen was then admitted and the flaskwas heated in an oil bath held at 95° C. Aliquots were periodicallywithdrawn under nitrogen flow. ¹H NMR analysis of the crude aliquotsindicated that >94% conversion of the monomer had been achieved after 2days. The flask was allowed to cool to ambient temperature, the residuewas dissolved in THF, and the polymer was precipitated by addition ofthe THF solution to swirled methanol held at 0° C. The resulting slurrywas cooled (−20° C.), centrifuged, decanted, and rendered free ofsolvent under vacuum overnight at 70° C. to provide 195 mg of poly-200(87% yield).

¹H NMR (500 MHz, d₆-acetone): δ 4.62-4.54 (m, 2.1H), 4.51-4.45 (m, 1H),4.38-4.28 (m, 3.8H), 2.29-2.23 (m, 1H), 2.05-1.99 (m, 1H), 1.94-1.87 (m,2.7H), and 1.83-1.68 (m, 3.3H).

IR (neat, selected peaks): 2957, 1770, 1729, 1159, 1122, and 1001 cm⁻¹.

DSC T_(g)=50° C. (See FIG. 20)

SEC PS-GPC (THF): M_(n)=3,630 g mol⁻¹, M_(w)=3,830 g mol⁻¹, D=1.06 (SeeFIG. 21)

Example 8. AIBN Initiated Free Radical Polymerization of Compound 300

A solution of the methacrylate ester 300 (70 mg, 0.216 mmol) and2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 1.1 mg, 6.7μmol) was prepared. After the full dissolution of AIBN in themethacrylate, the solution was transferred into a 5 mL round-bottomflask and degassed through a series of three freeze-pump-thaw cycles andsealed under vacuum. The reaction mixture was heated at 70° C. for 24 h.The reaction mixture was allowed to cool to ambient temperature to givean insoluble, clear disk.

IR (neat, selected peaks): 2960, 1770, 1724, 1188, 1169, and 1000 cm⁻¹.

DSC T_(g)=82° C. (See FIG. 22)

Example 9. Preparation of(±)-3-((3aR,6R)-1-Oxo-6,7-dihydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)propanoicacid (29)

Homoitaconic anhydride (28, 280 mg, 2.22 μmol) was suspended in furfurylalcohol (2, 217 mg, 2.21 μmol) and this slurry was allowed to stir(magnetically) at ambient temperature. After about 17 hours, thesuspension had turned to a light yellow solution. The residue waspurified by flash column chromatography on SiO₂ (hexanes/EtOAc, 3:1) togive 29 (245 mg, 50%) as a colorless oil.

¹H NMR (500 MHz, acetone-d₆) δ 11.05-10.35 (br s, 1H, COOH), 6.64 (d,J=5.8 Hz, 1H, H4), 6.62 (dd, J=5.9, 1.5 Hz, 1H, H5), 5.04 (dd, J=4.8,1.0 Hz, 1H, H6), 4.94 (d, J=11.0 Hz, 1H, C3H_(a)H_(b)), 4.55 (d, J=11.0Hz, 1H, C3H_(a)H_(b)), 2.49 (ddd, J=16.8, 11.3, 5.5 Hz, 1H,C9H_(a)H_(b)), 2.36 (ddd, J=16.8, 11.0, 5.3 Hz, 1H, C9H_(a)H_(b)), 2.28(dd, J=11.8, 4.8 Hz, 1H, C7H_(exo)H_(endo)), 1.94 (ddd, J=14.0, 11.0,5.5 Hz, 1H, C8H_(a)H_(b)), 1.43 (ddd, J=14.0, 11.3, 5.2 Hz, 1H,C8H_(a)H_(b)), and 1.38 (d, J=11.8 Hz, 1H, C7H_(exo)H_(endo)).

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made, while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula III or a salt thereof:

wherein: m is 1 or 2; R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl; andthe dashed bond is a single bond or double bond.
 2. A compound offormula I or a salt thereof, or a compound of formula II or anenantiomer thereof:

wherein R is R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl and each dashedbond is a single bond or double bond provided no two double bonds of thecompound of formula II are cumulated.
 3. The compound of claim 2 that isa compound of formula Ia or a salt thereof or an enantiomer thereof or asalt thereof, or a compound of formula II or an enantiomer thereof:


4. The compound of claim 2 that is a compound of formula Ia:

or a salt thereof or an enantiomer or a salt thereof.
 5. The compound ofclaim 2 that is a compound of formula Ic or Id:

or a salt thereof or an enantiomer or a salt thereof.
 6. The compound ofclaim 2 that is a compound of formula Ic or Id:

or an enantiomer thereof.
 7. The compound of claim 2 that is a compoundof formula II:

or an enantiomer thereof.
 8. The compound of claim 2 that is:

or a salt thereof.
 9. The compound of claim 2 that is:

or a salt thereof.
 10. The compound of claim 2 that is:

or a salt thereof.
 11. The compound of claim 2 that is:

or a salt thereof.
 12. The compound of claim 2 that is:

or a salt thereof.
 13. The compound of claim 2 that is:


14. A composition comprising:

or salts thereof.
 15. A method for preparing a compound of claim 2 whichis a compound of formula Ic1:

or a salt thereof or an enantiomer or a salt thereof, comprisingconverting furfuryl alcohol to the compound of formula Ic1 or a saltthereof or an enantiomer or a salt thereof.
 16. A method for preparing acompound of claim 2 which is a compound of formula Ic1:

or a salt thereof or an enantiomer or a salt thereof, comprisingconverting itaconic anhydride to the compound of formula Ic1 or a saltthereof or an enantiomer or a salt thereof.
 17. A method for preparing acompound of claim 2 which is a compound of formula IIa:

or enantiomer thereof comprising converting a compound of formula Ic:

or a salt thereof or an enantiomer or a salt thereof to the compound offormula IIa wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.
 18. Amethod for preparing 2-methylstyrene comprising converting a compound offormula Id:

or a salt thereof or an enantiomer or a salt thereof to 2-methylstyrene,wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.
 19. A polymercomprising two or more residues of formula 26a:

wherein: each m is 1 or 2; and each R is H, (C₁-C₆)alkyl, or(C₃-C₆)cycloalkyl; or a salt thereof.
 20. A method for preparing acompound of claim 2 which is a compound of formula Id:

or a salt thereof or an enantiomer or a salt thereof, comprisingconverting a compound of formula Ic:

or a salt thereof or an enantiomer or a salt thereof to the compound offormula Id, wherein R is H, (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl.